Mode of Action Frameworks
in Toxicity Testing and Chemical Risk
Mary Elizabeth Meek
Research included in this thesis was conducted as part of the author’s
responsibilities at Health Canada.
Meek, Mary Elizabeth 2009
Mode of Action Frameworks in Toxicity Testing and Chemical Risk
-with a summary in Dutch-
PhD thesis, Institute for Risk Assessment Sciences (IRAS), Utrecht University, the
Cover lay-out: Marije Brouwer, Division Multimedia of the Faculty of Veterinary
Medicine, Utrecht University, the Netherlands
Lay-out: Harry Otter, Division Multimedia of the Faculty of Veterinary
Medicine, Utrecht University, the Netherlands
Printed by: Ridderprint, Ridderkerk, the Netherlands
Mode of Action Frameworks
in Toxicity Testing and Chemical Risk
Het gebruik van analytische kaders
gebaseerd op de werking van stoffen bij
het testen van toxiciteit en de
(met een samenvatting in het Nederlands)
ter verkrijging van de graad van doctor aan de Universiteit Utrecht,
op gezag van de rector magnificus, prof. dr. J.C. Stoof,
ingevolge het besluit van het college voor promoties
in het openbaar te verdedigen
op dinsdag 1 oktober 2009
des middags te 12.00 uur
Mary Elizabeth Meek
geboren op 4 november 1954
te Kingston, Ontario, Canada
Promotoren: Prof. dr. W. Slob
Prof. dr. M. van den Berg
Table of contents
Historical Regulatory Context
Evolution of the Paradigm for Consideration of Hazard in
Chemical Risk Assessment
The Need for Analytical Frameworks for Human Relevance of
Mode of Action Consideration in Hazard Characterization and
Overview of this Thesis
Meek, M.E. and Armstrong, V.C. (2007) The assessment and
management of industrial chemicals in Canada, Risk Assessment
of Chemicals, Van Leeuwen, K. and Vermeire, T. Kluwer
Academic Publishers, Dordrecht, the Netherlands.
Meek, M.E., Patterson, J., Strawson, J. and Liteplo, R. (2007)
Engaging expert peers in the development of risk assessments.
Risk Analysis 27(6):1609-1621 and Erratum to “Engaging Expert
Peers in the Development of Risk Assessments” Risk Analysis,
Vol. 28(1): 249 (2008).
Meek, M.E. (2008) Recent developments in frameworks to
consider human relevance of hypothesized modes of action for
tumours in animals. Environmental and Molecular Mutagenesis
Meek, M. E., Bucher, J. R., Cohen, S. M., Dellarco, V., Hill, R. N.,
Lehman-McKeeman, L. D., Longfellow, D. G., Pastoor, T., Seed,
J., Patton, D. E. (2003) A framework for human relevance
analysis of information on carcinogenic modes of action. Critical
Reviews in Toxicology 33(6): 591-653.
Meek, M.E. (2001) Categorical default uncertainty factors -
Interspecies variation and adequacy of database. Human &
Ecological Risk Assessment 7: 157-163.
Meek, M.E. (2004) Toxicological highlight - Biologically motivated
computational modelling: Contribution to risk assessment.
Toxicological Sciences 82(1): 1-2.
Meek, M.E. (2005) Chemical-Specific Adjustment Factors (CSAF).
Encyclopedia of Toxicology, Elsevier.
Meek, B. and Renwick, A. (2006) Guidance for the development
of chemical specific adjustment factors - Integration with mode
of action frameworks. Toxicokinetics and Risk Assessment, Ed.
Lipscomb, J.C. and Ohanian, E.V., Informa Healthcare, New
Meek, M.E., Beauchamp, R., Long, G., Moir, D., Turner, L. and
Walker, W. (2002) Chloroform: exposure estimation, hazard
characterization, and exposure-response analysis, J. Toxicol.
Environ. Health B 5(3): 283-334.
Liteplo, R.G. and Meek, M.E. (2003) Inhaled formaldehyde:
Exposure estimation, hazard characterization and exposure-
response analysis. J. Toxicol. Environ. Health, B6(1), 85-114.
Evolution of Analytical Frameworks for Hazard Characterization
and Dose-Response Analysis
Expansion of the Frameworks: Addressing Combined Exposures
and Physiologically Based Pharmacokinetic Modelling
Implications for Testing:
Next Steps (Conclusions and Recommendations)
Recently, legislative mandates worldwide are requiring systematic consideration of
much larger numbers of chemicals. This necessitates more efficient and effective
toxicity testing, as a basis to be more predictive in a risk assessment context. This in
turn requires much more emphasis early in the design of test strategies on both
potential exposure and mechanism or modes of toxicity and a resulting shift in focus
from hazard identification to hazard characterization. This enables grouping of
substances and development of predictive computational tools.
It also requires a much better common understanding in the regulatory risk
assessment community of the nature of appropriate data to inform consideration of
mode of action and resulting implications for dose-response analysis and ultimately,
risk characterization. This requires a shift in focus from the previously principally
qualitative considerations of toxicological science to the necessarily more predictive and
quantitative focus of risk assessment. It also has implications for appropriate
communication and training of risk assessors.
Analytical frameworks such as those for human relevance of hypothesized
mode(s) of action (MOA/HR) and chemical specific adjustment factors (CSAF) are
important components in this evolution. They serve to better coordinate and integrate
input of both the research and regulatory communities in the translation of relevant
mechanistic data into quantitative characterization of risk. They also present essential
pragmatic tools in interim strategies to advance common understanding in these
diverse communities of appropriate application of data from evolving technologies.
The background to the critical role of these frameworks is introduced.
Research related to their development is described in the body of the thesis. The
critical role of the analysis which they promote in the evolution of more focussed,
efficient and effective, public health protective approaches is addressed in the
discussion. Recommendations for relevant next steps are also presented.
Historical Regulatory Context:
Modern chemicals legislation was introduced in Europe and North America in the
1970’s. In the intervening years, its focus has expanded with respect to the media of
interest (air, water, products), environmental as well as human health effects and
incrementally greater numbers of substances. The need to adopt a life cycle approach
to effectively manage the harmful effects of chemicals has also been increasingly
Introduction and/or renewal of early chemicals legislation focussed principally
on information requirements for New Chemicals. Resulting systematic consideration of
New Chemicals prior to their introduction into commerce encouraged the chemical
industry worldwide to minimize intrinsic hazard in the development of their products.
On the other hand, Existing Chemicals, i.e., those which were in commerce at the time
of introduction of relevant legislation, were “grandfathered”. That is, systematic
consideration of all as a basis to identify priorities for risk management was not
required, though a limited number were identified early for assessment.
This resulted in detailed assessments being conducted for several hundred
identified “Priority” chemicals within Canada and Europe over the past few decades. In
Canada, for example, it involved in depth evaluation of 69 substances (including
complex mixtures and groups) identified as priorities under the original and first
renewal of the Canadian Environmental Protection Act (CEPA -1988 and CEPA – 1999).
This transpired in two mandated five year timeframes between 1989 and 2000 [Meek,
2001; Meek, 1997; Meek, 1996; Meek and Hughes,1997; Meek and Hughes, 1995;
Meek et al.,1994]. These assessments were followed by the implementation of risk
management measures for a significant proportion that were deemed to present a risk
to the environment or human health.
More recently, mandates have required systematic consideration of priorities
for risk management from amongst all of the hundreds of thousands of existing
chemicals used worldwide. This is legitimately based on the likelihood that
unconsidered Existing Chemicals present potentially greater risk to health and the
environment than those introduced as New Chemicals following the advent of modern
For example, under the Canadian Environmental Protection Act (CEPA),
precedent-setting provisions were introduced to systematically identify priorities for
assessment and management from amongst the approximately 23, 000 substances
used commercially. This work was to be completed within a mandated 7 year time
frame between 1999 and 2006. This necessitated the development of innovative
methodology including evolution of the previously linear or sequential steps of risk
assessment and risk management to a more iterative approach where the need for,
and focus of, potential control options are identified at as early a stage as possible. It
has also required development of assessment products that efficiently dedicate
resources, investing no more effort than is necessary to set aside a substance as a
non-priority or to provide necessary information to permit risk management.
More recently, in Europe, a law entitled the Registration, Evaluation,
Authorisation and Restriction of Chemical substances (REACH) entered into force on 1
June 2007. Its objective is to effect greater parity between the consideration of New
and Existing Substances. This much broader consideration of Existing Chemicals, as
required under legislation in both Canada and Europe, necessarily has implications for
the efficiency of both testing and assessment.
Evolution of the Paradigm for Consideration of Hazard in Chemical Risk
Risk assessment i.e., the characterization of the potential adverse effects of human
exposures, is the requisite basis for the development and implementation of control
measures that are protective of public health (i.e., risk management), Traditionally, it
has been considered to be composed of four different elements: hazard identification
(i.e., the intrinsic capability of a chemical to do harm), dose-response assessment,
exposure estimation and risk characterization. The latter is a synthesis of relevant data
from all of the component steps with a clear delineation of uncertainties and their
implications for risk management.
This paradigm, proposed initially by the U.S. National Research Council in the
now infamous “Red Book” (NRC, 1983), is more than 25 years old. It is, perhaps, in
need of revisiting, given the essential shift in focus in chemicals risk assessment
necessitated by evolution in regulatory mandates. Specifically, the emphasis on hazard
identification must necessarily shift to hazard characterization. The latter involves a
comprehensive, integrated judgment of all relevant information supporting conclusions
regarding a toxicological effect including human relevance, but most importantly,
taking into account mechanistic information. This shift in focus from hazard
identification to hazard characterization is essential as a basis to avoid labor intensive
testing strategies which provide no or minimal data on mechanistic underpinnings of
observed toxicological effects. Continued reliance on studies designed to identify
hazard in animals at high doses without accompanying relevant mechanistic data
necessarily limits capability to predict risks to the public from exposure to chemicals
and the adequacy of resulting measures to protect public health.
Currently, toxicological studies focus on specific systems or types of effects.
Indeed, much effort and resources are invested currently in conducting and considering
the adequacy of toxicological studies on individual endpoints in experimental animals
(e.g., cancer, reproductive and developmental effects, etc.) as a basis to identify
hazard. There is, however, very little consideration at early stage in their design of
relevance to the prediction of risk. Rather, standardization has been emphasized as a
basis to ensure comparability of outcome. This has led often, to focus in assessment
on features of standardized study design based on criteria for their technical adequacy
in test guidelines as established by organizations such as the US Environmental
Protection Agency (USEPA) or OECD (Organization for Economic Cooperation and
Development). This includes aspects, for example, of whether the study adhered to
the principles of good laboratory practice, versus their relevance to risk assessment.
This is a function, likely, of the need for simplicity.
Since studies focus on particular systems or types of effects, weight of
evidence determinations in hazard identification relate to particular effects rather than
being integrated across systems. For example, consistency is considered in the context
of whether similar effects (e.g., cancer or reproductive) have been observed in other
studies or species. The types, specific site, incidence and severity of these effects and
the nature of the exposure- or dose-response relationship are also taken into account
in assessing weight of evidence for the observed effect. In assessing potential to
induce tumors, for example, aspects that add to the weight of evidence include
observation of uncommon tumor types, occurrence at multiple sites by more than one
route of administration in multiple strains, sexes and species, progression of lesions
from preneoplastic to benign to malignant, including metastases and comparatively
short latency periods. Consideration of contribution of the nature of changes in other
systems in the same animals, might, however, permit more informative and predictive
integration across biological systems, providing greater mechanistic insight.
Traditionally, also, weight of evidence descriptors for cancer and other effects
(principally mutagens and developmental/reproductive toxins) such as “carcinogenic to
humans”, “probably carcinogenic to humans” etc., have been developed by a number
of international organizations such as the International Agency for Research on Cancer
(IARC) and various national regulatory agencies including the US EPA and Health
Canada. These are delineated both as a basis for distinguishing approaches to dose-
response analysis in subsequent risk characterization and also as a basis to
communicate hazard. These characterizations represent, then, weight of evidence
determinations in hazard identification (i.e., intrinsic capability to cause harm) for
particular types of effects but are often misinterpreted to be risk-based (where
exposure, relevance and dose-response have been taken into consideration). In
recognition of this shortcoming, there is trend to providing more narrative and accurate
descriptors, which include reference to the conditions under which the effect is
observed, as a basis to avoid misinterpretation.
Undue emphasis on hazard identification as described above not only leads to
potential misinterpretation in the context of risk, but necessarily limits investment of
resources in more relevant and predictive components of risk assessment, such as
hazard and risk characterization. Given the need in future to be much more efficient
(and resultingly predictive in the context of human health risk), it seems essential to
focus early in testing and assessment on assimilation of information that informs in the
context of hazard characterization.
As indicated above, hazard characterization takes into account not only results
of traditional test guideline studies designed to identify hazard for individual endpoints
but additionally, mechanistic data, which are considered in the context of “mode” of
induction of toxic effects. In fact, an increasingly common understanding of the
concept of “mode of action” and its contrast with “mechanism of action” has been a
major area of advance in risk assessment. “Mode of action” is essentially a description
of the critical metabolic, cytological, genetic and biochemical events that lead to
induction of the relevant end-point of toxicity for which the weight of evidence supports
plausibility. “Mechanism of action”, on the other hand, implies a more detailed
molecular description of causality.
A postulated mode of action (MOA), then, is a biologically plausible sequence
of “key events” leading to an observed effect supported by robust experimental
observations and mechanistic data. Identification of “key” events – i.e., those that are
both measurable and necessary to the observed effect is fundamental to the concept
and the quintessential element of mode of action analysis. Delineation of the key
events in an hypothesized mode of action forces early interdisciplinary collaboration in
consideration and development of data. It is also a unifying theme in the various
components of risk assessment, imposing more explicit delineation of relevant
considerations for human relevance and subsequent dose-response analysis.
Mode of action as considered in this thesis (and the relevant frameworks
addressed herein) is comprised of both toxicokinetics (absorption, distribution,
metabolism and excretion) and toxicodynamics (interaction with target sites and the
subsequent reactions leading to adverse effects). This contrasts with previous
specification, for example, by the US EPA (2005), wherein it is stated that processes
that lead to formation or distribution of the active agent to the target tissue are
considered in estimating dose but are not part of the mode of action. Toxicokinetics is
included here as part of mode of action, given that often, the critical (and sometimes
rate limiting) early key event (i.e., that which is driving the process) involves metabolic
activation to a relevant toxic entity. Toxicokinetics is also included as a basis to
integrate rate limiting (key) steps in subsequent dose-response analysis, which is often
delivery of the parent compound to the target tissue and/or metabolism to the active
agent. It’s of interest in this context that while US EPA (2005) indicates that
toxicokinetics are excluded, mode of action statements in their assessments reference
both toxicokinetic and toxicodynamic aspects.
Information on mode of action is critically important to prediction of risk - in
determining relevance of observed effects in animals to humans, transitions in effect at
various doses and potentially susceptible subgroups. It is also critical as a basis to
address whether or not there is likely to be site concordance of effects between animals
and humans. While there is indication that, for example, growth control mechanisms at
the level of the cell are homologous among mammals, there is no evidence for nor
reason to believe that mechanisms for effects such as cancer induction are site
concordant. Rather information on likely variations between animals and humans in
toxicokinetics and toxicodynamics, based on understanding of mode of induction will
inform in this context. This information is essential also to integrate the results of
studies in animals and humans. For example, it is critical as a basis to interpret
(particularly) the significance of negative epidemiological data, taking into account the
sensitivity of the study to detect effects at most likely tumour sites in humans (i.e.,
which are not necessarily those observed in animals). It is also critical in the
development of relevant biomarkers in epidemiological studies, to increase their utility
as a basis for consideration of the risks to exposure to chemical in both the
occupational and general environments.
In hazard characterization, then, the weight of evidence of hazard integrating
information on mode of action for a spectrum of (often interrelated) end-points is
assessed critically but separately in order to define appropriate end-points for and
approaches to characterization of dose/concentration–response.
Dose- or exposure-response (dose/exposure-response) assessment, involves
quantitation of the probability that an exposure may result in a health deficit in a
population. This is necessarily based on characterization of hazards that are
considered critical and relevant to humans (i.e., those that are biologically relevant at
lowest doses). Advances in common understanding of the contrast of “mode of action”
(a less detailed description with emphasis on critical key events) with “mechanism of
action” (the molecular basis) and the pivotal role of “key events” in this context are
instrumental in encouraging more predictive testing and assessment as a basis for
better informed dose-response assessment. This includes taking into account the
shapes of the dose-response curves for the various key events (not just the adverse
effect, itself) and considering on the basis of the mode of action analysis, which of
these key events is likely to be rate limiting at various doses.
The toxicokinetic and toxicodynamic aspects considered in a mode of action
analysis are also potentially informative in quantitating interspecies differences and
variability within humans. Indeed, there is a continuum of increasingly data (mode of
action)-informed approaches to account for interspecies differences and human
variability, which range from default (“presumed protective”) to more biologically based
(“predictive”). The least data-informed option is incorporation of straight default
values, which incorporate no chemical or species-specific considerations. The basis for
such defaults is largely unknown. Cited support remains nebulous, though they are
sometimes justified, taking into account uncertain retrospective analyses of available
data on empirical relationships (Dourson and Parker, 2007).
Where data permit, categorical defaults, which permit more refinement
through delineation of categories based on, for example, characteristics of the
compounds themselves or of the species in which the critical effect has been
determined, can be developed. The latter include allometric (i.e., surface area to body
weight) scaling for different species or the approaches to development of reference
concentrations for inhalation for various types of gases/particles adopted by the U.S.
EPA (Jarabek, 1994). Additional data permit replacement of kinetic or dynamic
components of interspecies or interindividual variation with chemical specific
adjustments, based on comparative kinetic and dynamic parameters between animals
and humans or within humans. More quantitative toxicokinetic data may permit
development of a physiologically-based pharmacokinetic model (PBPK) which estimates
a "biologically effective dose” based on the mode of action and quantitative
physiological scaling taking into account, relevant chemical-specific physical chemical
properties and biological constants. Though rarely the case, where there is fuller
quantitative characterization of toxicokinetic and toxicodynamic aspects, a case specific
or biologically-based dose-response model can be adopted.
necessarily determined principally by the availability of relevant data. Availability of
relevant data has often been limited in the past, owing to the (perhaps unwarranted)
focus on the desire to repeat high dose studies designed to address hazard
Increasingly, for a limited number of Existing Chemicals identified as priorities
for assessment under early chemicals legislation, mode of action data have been
developed as a basis to reduce uncertainties in the areas of greatest inference in risk
assessment: namely, extrapolations across and within species (as a basis to identify
susceptible subgroups) and doses. For a limited number, biologically motivated case-
specific models or fully biologically based dose-response models that integrate
significant amounts of data have been developed. These advances and data have been
informative not only in the context of the individual chemicals, themselves, but also in
identifying patterns of effects associated with particular modes of action and their
implications for both human relevance and dose-response analysis.
In the vast majority of cases, however, even for substances for which there
are significant amounts of data on mode of action, default approaches to extrapolation
of dose-response and consideration of interspecies differences and human variability
are adopted in regulatory risk assessment. These approaches are described here.
Traditionally, then, default approaches
extrapolation are distinguished for effects for which it is believed that there may be a
probability of harm at all levels of exposure (e.g., interaction with DNA leading to
cancer) versus those for which it is believed that there is a level of exposure below
which effects will not be observed. The former approach is justified on the theoretical
basis that a single molecule could be sufficient to induce harm, if it interacts with the
These different assumptions generally lead to two distinct default approaches,
the first of which can result in a (highly uncertain) estimate of risk at various levels of
exposure (i.e., low dose risk estimates) and the second which results in development of
a “safe” dose (acceptable, reference or tolerable intakes). For the latter, this is a level
to which it is believed that a population can be exposed over a lifetime without adverse
effect. Both approaches to dose-response assessment are generally based on only two
to three data points in the experimental range, that is, in groups of animals exposed to
doses which exceed considerably those associated with most human exposures. The
relatively high exposures in toxicological studies designed to identify hazard have
traditionally been justified on the basis that only small numbers of animals per group
are surrogates for a much larger human population.
In the development of acceptable, reference or tolerable daily intakes (ADIs,
RFDs, TDIs) the experimental data are assessed to determine a level without adverse
effects (the no-observed-adverse-effect level or NOAEL). Alternatively, a curve is fitted
that best fits the central estimates of the relationship defined by these experimental
data points and confidence intervals are calculated. Reference or tolerable intakes are
commonly adopted for organ-specific, neurological, immunological, and reproductive-
developmental effects and carcinogenesis not induced by direct interaction with genetic
material. Without information on mode of action, however, there is no reason to
believe that this or the alternative (i.e., linear extrapolation) is more appropriate.
Development of a reference, acceptable or tolerable intake is traditionally
based, then, on an approximation of the threshold, through division of a no- or lowest-
observed-(adverse)-effect-level [NO(A)EL or LO(A)EL] by uncertainty factors (Dourson
The approach along this continuum adopted for any single substance is
1994, IPCS 1994, Meek et al. 1994). The NOAEL is the highest level of exposure that
causes no detectable adverse alteration of morphology, functional capacity, growth,
development or life span of the target organism in toxicological studies. Uncertainty
factors address interspecies differences, human variability and inadequacies of the
Increasingly, the benchmark dose or concentration (BMD/BMC) —an estimated
dose (or its lower confidence limit) associated with a particular effect level (e.g., 5 or
10% incidence or inhibition) for the critical effect—is adopted in lieu of an no or lowest
observed effect level. BMDs are estimated from fitted dose-response models which
describe the dose-response curve as a whole. This offers a number of advantages from
the perspective that BMDs/BMCs are not limited to the doses tested experimentally, are
less dependent on dose spacing, take into account more of the shape of the dose-
response curve, and provide flexibility in determining appropriate levels for biologically
significant changes. However, it should be noted that the quantitative impact of the
use of a No- or Lowest-Observed (Adverse) Effect Level versus a benchmark dose or
concentration on derived reference doses is rather limited in comparison with that
potentially resulting from relevant data on mode of action (kinetic or dynamic aspects)
to address components of uncertainty factors.
Alternatively, the magnitude by which the N(L)OAEL or BMC/BMD exceeds
estimated exposure (i.e., the margin of exposure or safety) is considered in light of
various sources of uncertainty (see, for example, Chapter 2).
Though commonly referenced as uncertainties, elements addressed in
development of the reference or tolerable dose or concentration or against which the
adequacy of the margin of exposure is judged include both uncertainty and variability.
The nature of the (principally) variability addressed includes interspecies differences
and intraspecies (interindividual) or human variability. Inadequacies of the database
such as missing data on specific endpoints (uncertainty) are also commonly taken into
The default “uncertainty” factor for interspecies differences can be considered
to convert the no or lowest effect level or benchmark dose/concentration for animals
(derived from a small group of relatively homogeneous test animals) into the no or
lowest effect level or benchmark dose/concentration anticipated for an average
representative healthy human. It is generally 10 fold. Although data on adverse
effects in humans can be used directly without the need for a factor for interspecies
differences, the paucity of such data results in the vast majority of risk assessments
being based on studies in experimental animals. The default uncertainty factor for
human variability converts the no or lowest effect level or benchmark
dose/concentration for the average human into a no or lowest effect level or
benchmark dose/concentration for susceptible humans. It is also generally 10 fold.
These default values have been used for over 40 years (with limited
reconsideration) by both national agencies and international bodies such as the Joint
FAO/WHO Committee on Food Additives and Contaminants (JECFA) and the Joint
FAO/WHO Meeting on Pesticide Residues (JMPR) as a basis to derive ADIs, TDIs or RfDs
for the general population. There is, however, very limited support for these default
values whose use continues to be justified based principally on uncertain retrospective
historical analyses of limited databases.
At present there is no clear consensus on appropriate methodology for
dose/exposure-response assessment of chemicals for which a probability of harm at
any level of exposure is assumed (e.g., carcinogens that interact directly with genetic
material and germ cell mutagens). Options include:
1) expression of dose/exposure–response as potency in or close to the experimental
2) estimation of risks in the low-dose range through linear extrapolation from an
3) calculation of the margin of exposure, and
4) advice that control measures should be introduced to reduce exposure to the
maximum extent practicable (Younes et al., 1998).
In Canada in the Priority Substances Program, for example, dose or exposure
response is expressed as potency in or close to the experimental range. This approach
was adopted primarily in recognition of the potentially misleading precision associated
with expression of risk in the low-dose range in absolute terms (as numbers of cases
per unit of the population). Expression in this form has potential to obfuscate the
considerable uncertainties associated with linear extrapolation from animals over as
much as 6 orders of magnitude (Health Canada 1994; Meek et al., 1994). Rather,
quantitative measures of potency in the experimental range are considered more in a
relative or priority setting context. This is also the case in Europe (EU, 2003). In the
U.S. Environmental Protection Agency cancer guidelines (US EPA, 2005), risks in the
low-dose range for such cases are estimated through linear extrapolation from an
effective dose in the experimental range.
Consideration of endpoints more in the context of their mode of action
necessarily blurs the currently rather arbitrary distinction in default approaches to
dose-response characterization between cancer and noncancer (Meek, 1997). Rather,
extrapolation for either would be based on more comprehensive understanding of the
nature of the dose-response relationship for rate limiting key events. Appropriate
defaults in the absence of sufficient data to support development of biologically
motivated case-specific or fully biologically based dose-response models may involve
linear extrapolation for some noncancer effects and development of reference doses or
margins of exposure for tumors or precursor lesions.
The Need for Analytical Frameworks for Mode of Action Consideration in
Hazard Characterization and Dose-Response Analysis
There is, then, rather a significant gap between the current approaches to toxicity
testing and risk assessment and the need to be predictive to meet imposing mandates
for priority setting and assessment of large numbers of chemicals, with limited
resources. This results from traditional focus principally on hazard identification in
(standardized) toxicity testing and (simple) default approaches to dose-response
characterization in risk assessment. And while generic default approaches (e.g.,
subdivision of effect levels from high dose animal studies by often 100 or more fold
values or low dose linear extrapolation from much higher doses) are commonly
presumed protective, this has not been well tested. The premise is also inconsistent
with what is known about the impact of results from targeted and coordinated
investigations of mode of action which have supported more data derived approaches
(e.g. chemical specific kinetic and dynamic data that indicate that appropriate
adjustments may be more or less than default).
the nature of toxicity testing (addressing principally hazard identification) and
associated reliance on default approaches in risk assessment, then, presents a
considerable barrier to meeting current regulatory challenges. Indeed, the principal
reason that the potential predictive capability of (quantitative) structure activity
relationship analyses (Q)SARs for human health risk assessment including the (non-
automated) Threshold of Toxicological Concern is limited, relates to the absence of
underpinning in a mode of action context.
Our reliance on default while resulting principally from the (undue) focus on
hazard identification in toxicity testing and the desire for simplicity, is also often a
function of the inadequacy of mechanistic data. This information is sometimes
collected in a largely unfocussed and uncoordinated manner in a risk assessment
context. In addition, owing to the principal reliance on default, there has been
inadequate transparency on the types of information that would be more informative
(i.e., specification in risk assessment of critical data gaps that would meaningfully
inform mode of action considerations).
Moreover, even in cases where there are considerable robust mechanistic data
to inform quantitative risk assessment, they are often not used in regulatory
applications. This is sometimes a function simply of lack of understanding of the
regulatory risk assessment community and/or regulatory pressures to conduct
assessments in very limited timeframes. Alternatively, it is often due to a shortage of
interdisciplinary consultation of risk assessors (who commonly have backgrounds
principally in toxicology), modelers and those that conduct mechanistic investigations.
Improved communication between the various groups and interdisciplinary training
would seem to be critical in this context. Occasionally, it is related to a lack of
transparency in the separation of science judgment from science policy choices (i.e.,
with default being considered to be more public health protective).
The focus of this thesis, then, is to review the state of development of
analytical frameworks for consideration of the weight of evidence for the human
relevance of mode of action and implications for dose-response analyses in the context
of their essential contribution as a basis to increase common understanding between
the risk assessment and research communities. Additionally, their evolving and
expanding content and use is considered in the context of essential more progressive
toxicity testing strategies to meet expanded regulatory mandates (Figure 1).
This lack of predictive capacity in the context of human health risks owing to
• Curve fitting at high dose
for point of departure for
late (apical) endpoints
• Linear extrapolation or
• N/LO(A)EL or BMC/D
• More realistic doses
• Earlier endpoints
Figure 1. Moving from Default to More Mode of Action Based Approaches in Chemical Risk Assessment
Overview of this Thesis
This thesis is comprised of this Introduction, ten chapters representing individually
published studies and a final chapter that provides a discussion of the key points. Also
included in the final chapter are suggested next steps in increasing efficiency and
effectiveness of chemical risk assessment through increased development and uptake
of biological data.
Initially, the historical and evolving regulatory context of chemical risk
assessment is addressed (Chapter 2) as a basis for understanding the need for
considerable increase in efficiency and effectiveness and associated strategies for
Chapter 3 addresses advances in process for preparation of chemical
assessments in the area specifically of peer engagement. This is essential to
consideration of increasingly biologically motivated vs. default approaches in hazard
characterization, dose response analyses and risk characterization. The requirement
under the Canadian Environmental Protection Act to set priorities from amongst
thousands of existing chemicals has provided opportunity for incorporation of efficient
and increasingly complex peer involvement in both assessments of individual or groups
of substances. Specifically, this has involved more formal peer input at the earlier
stages of development and greater complexity of peer input, consultation, and peer
review for complex issues. This approach maximizes efficiency in acquiring necessary
early multidisciplinary input while maintaining the defensibility of output.
In chapter 4, the continuing evolution of Mode of Action Human Relevance
Frameworks (MOA/HR) as a basis to systematically consider the weight of evidence of
hypothesized modes of action in animals and their potential human relevance for both
cancer and non-cancer effects is described. Chapter 5 outlines in detail the basis and
nature of the expansion of previous frameworks considering the weight of evidence for
modes of action in animals to relevance to humans. This is based on systematic
evaluation of comparability between key events in animals and humans taking into
account chemical specific data and more generic information on, for example, biology,
physiology and human disease models. The chapter includes several case studies
representing several different examples of application of the human relevance
component of the framework.
While developed and refined initially to consider principally hazard
characterization, MOA/HR frameworks have been extended recently to consider
implications for dose-response analysis. Chapter 6 addresses the continuum of
increasingly mode of action informed approaches in dose-response analyses from
default (“presumed protective”) to more predictive options. Chapter 7 outlines the
contribution of the most highly evolved of these options, namely a biologically
motivated computational model for formaldehyde. Chapter 8 described the objectives
and nature of a less data intensive mode of action driven approach on this continuum,
namely derivation of chemical specific adjustment factors as a basis to incorporate
partial data on kinetics and/or dynamics to replace default. Chapter 9 provides an
illustration of integration of the frameworks for human relevance analysis of mode of
action and chemical specific adjustment factors.
Chapters 10 and 11 address the implications for risk characterization of
MOA/HR analysis in hazard characterization and extension to dose-response analysis
through provision of examples for two specific chemicals. For the first, namely
chloroform, available data on mode of action indicate that non-cancer precursor effects
(i.e., sustained cytotoxicity and regenerative cellular proliferation in the kidney and
liver) are likely protective for cancer and for the second, namely formaldehyde, dose-
response analysis takes into account both early interaction with DNA and
cytotoxicity/regenerative cell proliferation in the development of nasal tumors in rats.
Dourson, M.L. 1994. Methods for establishing oral reference doses. In: Risk Assessment of Essential
Elements, pp. 51-61. (Mertz, W., Abernathy, C.O. and Olin, S.S, Eds.).
Dourson, M.L. and Parker, A.L. (2007) Past and Future Use of Default Assumptions and Uncertainty
Factors: Default Assumptions, Misunderstandings, and New Concepts. Human and Ecological
Risk Assessment, 13: 82–87.
Jarabek, A.M. 1994. Inhalation RfC methodology: Dosimetric adjustments and dose-response estimation of
noncancer toxicity in the upper respiratory tract. Inhal. Toxicol. 6 (suppl): 301-325.
Health Canada (1994) Human Health Risk Assessment for Priority Substances. ISBN: 0-662-22126-5 Cat.
No.: En40-215/41E, http://www.hc-sc.gc.ca/ewh-semt/pubs/contaminants/approach/index-
International Programme on Chemical Safety (IPCS), 1994. Environmental Health Criteria 170: Assessing
human health risks of chemicals: Derivation of guidance values for health-based exposure
limits, Geneva, WHO.
IPCS. 2005. Chemical-specific adjustment factors for interspecies differences and human variability:
Guidance document for use of data in dose/concentration-response assessment. Harmonization
Project document no. 2. World Health Organization, Geneva
Meek, M.E. (2001) Risk assessment methodologies: Trends and Needs - An international perspective. ILSI
Monograph on Microbial Pathogens and Disinfection Byproducts in Drinking Water: Health
Effects and Management of Risks, ILSI Press, Washington, pp. 341-350.
Meek, M.E. (1999) Application of uncertainty factors in the Priority Substances Program and international
harmonization. Human & Ecological Risk Assessment 5: 1013-1022.
Meek, M.E. (1997) Perceived precision of risk estimates for carcinogenic versus non-neoplastic effects:
implications for methodology. Human & Ecological Risk Assessment 5: 673-679.
Meek, M.E. (1996) Assessment of priority substances under CEPA - Variation in exposure and response.
Environmental Toxicology and Pharmacology 2:111-114.
Meek, M.E. and Hughes, K. (1997) Approach to risk assessment for Priority Substances in Canada: Novel
Aspects. Proceedings of the Symposium on Harmonization of State/Federal Approaches to
Environmental Risk, East Lansing, MI, Ed: M.A. Kamrin, John Wiley & Sons, 308 pp.
Meek, M.E. and Hughes, K. (1995) Approach to health risk determination for metals and their compounds
under the Canadian Environmental Protection Act. Regulatory Toxicology and Pharmacology
Meek, M.E., Newhook, R., Liteplo, R.G. and Armstrong, V.C. (1994) Approach to assessment of human
health risk for Priority Substances under the Canadian Environmental Protection Act. Journal of
Environmental Science and Health C12: 105-134.
NRC (U.S. National Research Council) (1983) Risk assessment in the federal government: managing the
process. Committee on the Institutional Means for Assessment of Risks to Public Health,
Commission on Life Sciences, NRC. Washington, DC: National Academy Press.
Renwick, A.G. Data-derived safety factors for the evaluation of food additives and environmental
contaminants. Food Addit Contam 1993; 10:275-305.
Younes, M., Sonich-Mullin, C., Meek, M.E., Hertel, R., Gibb, H. and Schaum, J. (1998) Risk: Assessment
and Management. International Occupational and Environmental Medicine, Mosby, 768 pp.
US Environmental Protection Agency (US EPA) (2005). Guidelines for Carcinogen Risk Assessment.
Washington, DC, EPA/630/P-03/001F.
The Assessment and Management of
Industrial Chemicals in Canada
Meek, M.E. and Armstrong, V.C. (2007)
Risk Assessment of Chemicals
Van Leeuwen, K. and Vermeire, T.
Kluwer (Eds) Academic Publishers, Dordrecht, the Netherlands
The chemical industry is one of the largest manufacturing sectors in Canada and
employs more than 90,000 people; nearly every major global chemical company in
the world has production or research and development facilities. In 2003, more than
two thousand companies, including 21 of the 25 world’s largest manufacturers, had
operations in this country; shipments of chemical products were worth $42 billion
(~26.4 billion €). The industrial chemicals sub-sector, which includes companies
manufacturing petrochemicals, industrial gases, pigments, other inorganic and
organic chemicals, resins, and synthetic fibres, accounted for close to 50% of this
In this Chapter, emphasis is placed on the progressive, legislated
requirements for assessment and control of significant numbers of existing
substances under the Canadian Environmental Protection Act (CEPA) , which
include emissions and by-products associated with chemicals production. This has
involved the in-depth assessment of 69 substances (including complex mixtures and
groups of substances) identified as priorities under the first CEPA (CEPA-1988)  in
two mandated five year timeframes. These assessments were followed by the
implementation of risk management measures for a significant proportion that were
deemed to present a risk to the environment or human health.
More recently, under CEPA–1999 , precedent-setting provisions to
systematically identify, in a timely manner, priorities for assessment and
management from among the approximately 23, 000 existing commercial substances
have been introduced. This has necessitated the development of innovative
methodology including evolution of the previously linear or sequential steps of risk
assessment and risk management to a more iterative approach where the need for,
and focus of, potential control options are identified at an early stage of assessment.
It has also required development of assessment products that efficiently dedicate
resources, investing no more effort than is necessary to set aside a substance as a
non-priority or to provide necessary information to permit risk management.
Similarities to, and variations from, approaches adopted or contemplated under US
and European chemicals control legislation are also outlined.
It is to be stressed that the nature of the actions taken under CEPA-1999
and the associated methodological developments necessitated by the provisions of
this Act continue to evolve. Therefore this Chapter can provide only an overview of
the status of industrial chemicals management as it was at the time of its completion,
that is, early in 2007. Additional detail and further developments are and will be
available at website references listed in the bibliography.
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Canada is a federation of ten provinces and three territories, for which responsibilities
for matters pertaining to the environment are shared. Indeed, the Supreme Court of
Canada has ruled that environmental protection is of such importance that it requires
action by governments at all levels. In January, 1998, the provinces, with the
exception of Quebec, and the federal government signed an Accord on Environmental
Harmonization, which sets the framework for collective goals and action to protect
the environment [5, 6]. The Canadian Environmental Protection Act (CEPA), the
cornerstone of federal environmental protection, is entirely consistent with the
Harmonization Accord and is the tool for implementation of Harmonization
International aspects of the assessment and control of toxic chemicals fall
under the purview of the federal government; these include responsibilities related to
international air and water pollution and participation in international initiatives of,
for example, the International Programme on Chemical Safety, the United Nations
Environment Programme and the Organization for Economic Cooperation and
CEPA has been structured to avoid duplicating effective measures that have
already taken or are proposed to be taken by other federal and provincial
departments or ministries. Should an assessment conducted under CEPA indicate the
need to take action to protect health or the environment and should such action not
be undertaken under other Canadian statutes, the risk management provisions of
CEPA can be invoked. Any actions that are to be taken under other legislation as a
result of initiatives under CEPA must be deemed to be equivalent to those proposed
under this Act. In order to coordinate work with the provinces and avoid duplication,
especially with respect to the development of regulations, a National Advisory
Committee has been established as required under CEPA-1999.
With respect to assessment and control of the environmental and public
health impacts of new substances, (an area in which the provinces and territories do
not have a mandate), actions taken under other federal statutes must be equivalent
in terms of requiring notification prior to import into, or manufacture in, Canada and
assessment of potential risks to both the environment and human health. These
equivalency provisions have had an impact on the assessment and control of
substances that fall under the purview of federal legislation such as the Food and
Drugs Act , the Feeds Act  and the Fertilizers Act .
2.2 Evolution of the Canadian Environmental Protection Act
In contrast to some of its other health protection statutes such as the Food and
Drugs Act which dates back to 1920, Canada’s environmental protection laws have
been developed relatively recently. The Department of the Environment was created
in 1972 and the first federal environmental protection act, the Environmental
Contaminants Act (ECA)  “An Act to Protect Human Health and the Environment
from Substances that Contaminate the Environment.” was promulgated in 1975. This
legislation, like its successors, was administered jointly by the Department of Health
and the Department of the Environment and was developed, in part, to provide a
Federal-provincial regulatory structure
means to respond domestically to international environmental initiatives such as
those being undertaken by the Organization for Economic Cooperation and
Development (OECD) to control polychlorinated biphenyls (PCBs). A number of other
substances of concern at that time (e.g., polybrominated biphenyls, polychlorinated
terphenyls, mirex, and lead from secondary lead smelters, asbestos and mercury),
were subsequently banned or controlled under the ECA.
While the ECA required companies to identify chemicals not previously used
as “new” there was no systematic testing or assessment of chemicals for toxic effects
prior to their introduction. “New” was defined as previously unused by the company
and while relevant quantities were also to be specified, notification was required only
after introduction of the substances into commerce. Submission of information and
testing by industry could be required only if the Ministers of Health and of the
Environment had “reason to believe that a substance is entering/may enter the
environment in amounts that are a danger to health or the environment” based on
consideration of information that had already been generated or obtained from other
sources. While information on a large number of new chemicals was examined, the
administrative procedure for effecting control was complex and therefore none was
undertaken through the short history of the program.
Proposals from an Environmental
Consultative Committee (ECAACC) [11,
Parliamentary review of the ECA and the Canadian Environmental Protection Act
(CEPA), “An Act Respecting the Protection of the Environment and of Human Life and
Health”, came into force in 1988. CEPA-1988, a much more comprehensive piece of
environmental protection legislation, not only superseded the Environmental
Contaminants Act, but also subsumed other Canadian environmental protection
statutes (and their regulations) such as the Clean Air Act, the Ocean Dumping
Control Act, part of the Canada Water Act and part of the Department of the
Environment Act into a single piece of legislation. One of the salient new features of
this Act was embodiment of the notion of pre-import/ pre-manufacture notification
and assessment of new substances including biotechnology products with adoption of
a minimum data set based on that developed under the Chemicals Programme of the
OECD . CEPA-1988 was first passed into law in June, 1988, amended in June,
1989 and was replaced with a new and further expanded Act which received royal
assent in September, 1999 (CEPA-1999), following a review of its operation and
implementation as required to be undertaken within 5 years of the promulgation of
2.3 The current Canadian Environmental Protection Act (CEPA-1999)
CEPA-1999 is entitled "An Act Respecting Pollution Prevention and Protection of the
Environment and Health in order to Contribute to Sustainable Development” . New
principles to guide the application of this Act are spelled out in its preamble; thus in
implementing the various provisions of CEPA, Environment Canada and Health
Canada are expected to ensure:
that consistency between federal government departments and collaboration
with other jurisdictions results in effective and integrated approaches, policies
and programs to manage the health and environmental risks of toxic
during considered the
RISK ASSESSMENT OF CHEMICALS
recognition that the risks from toxic substances is a matter of national concern
that transcends geographic boundaries;
that the importance of an ecosystem approach is recognised;
that that there is a commitment to implement pollution prevention as a national
goal and as the primary mechanism to promote environmental protection;
that the Government of Canada is able to fulfil its international obligations in
respect of the environment;
implementation of the precautionary principle;
implementation of the “polluter pay” principle; and
that there are public participation, openness and transparency in decision-
making and that there are mechanisms available for supporting these goals.
Prevention and management of risks posed by toxic and other harmful
substances remain as the principal objectives of the revised CEPA. The provisions for
implementing pollution prevention, investigating and assessing substances,
controlling toxic substances, and those for fuels, international air and water
pollution, motor emissions, nutrients, environmental emergencies, for regulating the
effects of the federal government’s own operations and waste disposal at sea and the
import and export of wastes were added or expanded upon. Recognition of the
growing importance of biotechnology led to the creation of a specific section with
provisions that parallel those for chemical substances.
CEPA-1999 also provides for the gathering of information for research and
the creation of inventories of data and for the development of environmental
objectives, guidelines and codes of practice. In addition, new rights were bestowed
on Canadians to participate in decisions on environmental matters, including the
ability to compel investigation of an alleged contravention of the Act and the
possibility of bringing civil action when the government is not enforcing the law.
Aboriginal governments have the right to be represented on a National Advisory
Committee which must be established as a way of “enabling national action to be
carried out taking cooperative action in matters affecting the environment and for the
purposes of avoiding duplication in regulatory activity among governments”.
The new CEPA contains 343 operative sections and six schedules, and is
divided into the parts shown in Table 1:
Table 1. The operative parts of CEPA-1999
2 Public Participation
3 Information Gathering, Objectives, Guidelines and Codes of Practice
4 Pollution Prevention
5 Controlling Toxic Substances
6 Animate Products of Biotechnology
7 Controlling Pollution and Managing Wastes
8 Environmental Matters Related to Emergencies
9 Government Operations and Federal and Aboriginal Land
11 Miscellaneous Matters
Responsibility for the administration of CEPA is shared between Canada’s Department
of the Environment and Department of Health. The Minister of the Environment has
overall responsibility for the administrative aspects of the Act and for most of its
other provisions, notably those for enforcement and compliance. Also in most of the
instances where the Minister of Health is named, responsibilities must generally be
carried out collaboratively. These joint responsibilities include assessing and
controlling toxic substances and assessing the impacts of (international) air pollution,
and (international) water pollution. The Minister of Health can act independently in
conducting health-related research investigations and other studies, setting
environmental objectives, guidelines and codes of practice to protect health, and in
establishing advisory committees with respect to these responsibilities. It has also
been customary for the Health Department to provide advice to Environment Canada
on health related issues arising under parts of the Act in which the Health Minister is
not explicitly named, (e.g., with respect to the potential health effects of fuels and
vehicle, engine and equipment emissions).
2.5 The CEPA definition of “Environment”
The definition of “environment” in CEPA is sufficiently broad to encompass the
occupational as well as the general environment; however, since the provinces and
territories are generally responsible for the health and safety of their workers,
assessments of the impacts on health of substances under CEPA have been confined
to those on members of the general public.
d. the interacting natural systems that include components referred to in paragraphs (a) to (c).
Administration of the CEPA
Box 1. CEPA definition of “environment”
“Environment” means the components of the Earth and includes
a. air, land and water;
b. all layers of the atmosphere;
c. all organic and inorganic matter and living organisms; and
Canada’s environmental protection strategy is based on sustainable development; a
key component of this is controlling substances that can be harmful to human health
or the environment in order to ensure that the risks are prevented or reduced.
CEPA-1999 requires the Minister of the Environment, in carrying responsibilities with
respect to Toxic Substances, “…to the extent possible, to cooperate and develop
procedures with jurisdictions other than the Government of Canada, (that is other
governments in Canada or those of member states of the Organization for Economic
Cooperation and Development), to exchange information respecting substances that
are specifically prohibited or substantially restricted by, or under, the legislation of
those jurisdictions for environmental or health reasons”.
Controlling toxic substances is viewed as a two phase process, risk
CEPA’s PROVISIONS FOR TOXIC SUBSTANCES
RISK ASSESSMENT OF CHEMICALS
assessment and risk management. The first of these entails a science-based
evaluation to enable decision-making on whether a substance poses a risk to health
or the environment; the second phase identifies the most suitable control measures
. The Act provides a framework for the identification and control of existing
substances and management of those considered to pose a risk to human health
and/or the environment. This framework is broad, transparent and evidence-based,
taking into account aspects (i.e., exposure and effects) of a substance in relation the
potential risk it may pose.
3.1 Definitions of “Toxic” and “Substance”
The broad definition of “substance” under CEPA encompasses not only discrete
(industrial) chemical compounds but also complex mixtures formed naturally or as a
result of chemical reactions, emissions and effluents and products of biotechnology.
All such substances are therefore candidates for assessment under the legislation.
Animate biotechnology products can be whole organisms, or parts, or products of
organisms, including those developed through genetic engineering. The definition of
“substance” is somewhat more restrictive with respect to "new substances" in that
articles, physical mixtures and effluents and emissions are excluded.
Box 2. CEPA definition of “substance”
"Substance" means, in part: "any distinguishable kind of organic or inorganic matter, whether
animate or inanimate, and includes ....any mixture that is a combination of substances.....,....any
complex mixtures of different molecules that are contained in effluents, emissions or wastes that
result from any work, undertaking or activity."
Box 3. CEPA definition of “toxic”
A substance is "toxic" if it is “...entering or may enter the environment in a quantity or concentration
or under conditions that:
a have or may have an immediate or long-term harmful effect on the environment or its
b constitute or may constitute a danger to the environment on which life depends; or
c constitute or may constitute a danger in Canada to human life or health.
The purpose of carrying out an assessment under CEPA is to determine
whether a substance is or is not "toxic". The definition of “toxic” is a legal one and
embodies the notion that the ability of a substance to harm the environment or
human health is a function of its release into the environment, the intrinsic toxicity
(i.e. toxicity in the traditional sense) and the concentration of the substance to which
a person, (or other environmental receptor), is exposed. Also, inclusion of the word
"may" in the definition with respect to both entry into the environment and the
potential danger or harm (i.e., effects) allows the approach to designating "toxic" to
be developed in a manner which takes into account uncertainties and is consistent
with the generally accepted principles of health risk assessment. Thus, "risk" is
considered more precisely as depending on the nature of the possible effects and the
likelihood of their occurrence; the probability (that any given effect will occur) in turn
is a function of the potency of the toxicant, the susceptibility of the exposed
individual, or species, and the level of exposure.
The existence of information that is consistent with the designation of a
substance as "toxic" under the Act sets the stage for reviewing options for controlling
risks to human health and/or to the environment and, hence, for adding the
substance to Schedule I of CEPA (the "List of Toxic Substances").
3.2 Provisions for new substances and the Domestic Substances List
Under the New Substances Program, companies or individuals wishing to import or
manufacture substances that are new to Canada must notify the government of that
intent so that the substances can be assessed for possible effects on the
environment and human health; certain information specified in regulations must
also be provided [14,15]. The New Substances Notification Regulations for chemicals
and polymers first came into force in July, 1994; in October, 2005, these were
replaced with amended regulations.
The new substances provisions were a critical component in the introduction
of CEPA-1988 since they allowed Canada to meet its obligation to honour the OECD
Council Decision  concerning the requirement for a Minimum Pre-market Data
Set for assessing new chemicals. CEPA allows for the control of a new substance
before it is manufactured or imported whenever there is a “suspicion” that the
substance is “toxic” under the Act.
In order to distinguish commercial substances that are new to Canada and
those already in use, a Domestic Substances List (DSL)  was compiled under
CEPA-1988; the DSL included some 22,400 substances nominated to Environment
Canada that were, between January 1, 1984, and December 31, 1986:
in Canadian commerce;
used for commercial manufacturing purposes; or,
manufactured in, or imported into, Canada in a quantity of 100 kg or more in
any calendar year.
Substances on the DSL are referred to as “existing” substances. (Under
CEPA, an existing substance can also be one that is released as a single substance,
an effluent, a mixture or a contaminant in the environment.) A Non-domestic
Substances List (N-DSL)  was also compiled for substances not on the DSL but
believed to be in international commerce, though not in Canada, during the reference
period. The N-DSL was based on the 1985 Toxic Substances Control Act Inventory
(excluding DSL entries), published by the US EPA, chosen as representative of
substances that were in commercial use in an "ecozone" similar to that of Canada
over the 1984-1986 reporting period . The N-DSL now comprises more than
58,000 substances and is updated bi-annually. Information requirements for substances
which are listed on the N-DSL when notified as new to Canada are reduced. [For
additional information, see http://www.ec.gc.ca/substances/nsb/eng/home_e.shtml].
The DSL is amended from time to time to include new substances that have
been assessed for their risks to human health and the environment and which are
deemed not to require the imposition of conditions; substances for which a SNAc
provisions (See Section 3.7) have been imposed can also be added.
Between January, 1987 and the coming into force of the New Substances
Notification Regulations for chemicals and polymers (July, 1994), about 4,400
RISK ASSESSMENT OF CHEMICALS
commercial chemicals were imported into, or manufactured in, Canada; CEPA-1988
included transitional provisions for post-market notification of these substances.
Substances that are not on the DSL or the N-DSL cannot be imported into, or
manufactured in, Canada in quantities greater than those stated in the NSNR
(Chemicals and Polymers) until prescribed information has been notified to
Environment Canada. These regulations specify the information that must be
provided to meet the notification obligations; the main features are :
establishment of categories of substances (e.g., chemicals, biochemicals,
polymers, biopolymers, and organisms);
identification of administrative and other information requirements;
specification of conditions, test procedures and laboratory practices to be
followed in developing test data;
timing of notification before manufacture or import or activity outside the scope
of a previously issued SNAc Notice; and
assessment periods for the submitted information.
The establishment of different categories of substances enables different
levels of notification requirements to be established depending on the characteristics
of the substance and the quantities in which it is to be imported or manufactured.
Thus, substances are first generally categorized by type (i.e., chemicals,
polymers, biopolymers or organisms) and, then, each substance type is further
separated into notification groups based on factors such as use, volume of
manufacture or import use and whether the substance is on the N-DSL Eight
Schedules of information requirements are specified for chemicals and polymers and
one for biochemicals and biopolymers under the NSNR (Chemicals and Polymers)
. There are reduced requirements for special category substances, those for
research and development, contained site-limited intermediates and contained for
export only. There are also reduced requirements for certain polymers that meet the
“reduced regulatory requirement” criteria. Additional information may be required for
chemicals and polymers released to the aquatic environment in high quantities or to
which the public may be significantly exposed. The most comprehensive data
package is required for substances that are not on the N-DSL and are to be imported
or manufactured in a quantity greater than 10,000 kg/year.
Box 4. Possible outcomes of the assessment of information
The possible outcomes of the assessment of information submitted are:
a determination that the substance is not toxic or capable of becoming toxic;
a determination that the substance is toxic or capable of becoming toxic;
a determination that the substance is not toxic or capable of becoming toxic, but a suspicion
that a significant new activity in relation to the substance may result in the substance
If the substance is not suspected to be toxic, the notifier may import or
manufacture the substance after the assessment period has expired. Where the
substance is suspected of being toxic, or becoming toxic, the government may take
measures under the Act to ensure that the substance is handled in ways that will
adequately manage these risks. These measures could include imposing conditions
under which the substance may be used, prohibiting import or manufacture of the
substance or requesting additional Information or test results that would enable a
determination of whether or not the substance is toxic. If the substance is not
suspected to be toxic but could become so by means of a significant new activity, it
can be subject to a re-notification through the issue of a Significant New Activity
(SNAc) Notice (See Section 3.7).
The time periods that Health Canada and Environment Canada have to
assess the notified information and to impose any controls prescribed within the
NSNR (Chemicals and Polymers) and the NSNR (Organisms) vary depending on the
notification requirements and range from 5 to 75 days for chemicals and polymers
, and 30 to 120 days for organisms . Failure to assess a new substance
within the legislated time period automatically permits the manufacture or import of
the substance in(to) Canada with no (environmental) restrictions on how it can be
used. In such cases, CEPA still provides measures for addressing the substance, even
though the time period for assessment has expired and the substance has been
added to the DSL.
The New Substances Program is regarded as a first line of defence against
the release of harmful substances into the Canadian environment; the notification
regulations are seen as an integral part of the federal government’s national pollution
prevention strategy. Approximately 800 substances new to the Canadian
marketplace are assessed annually .
3.3 Provisions for existing substances
Under Part II of CEPA-1988, a framework for systematically determining the toxicity
of substances deemed to be of high priority was implicit in the legislation. Thus, the
Ministers of Health and the Environment were required to establish a list of
substances (the Priority Substances List) deemed to be of highest concern with
respect to health or the environment and to assess the risks of these substance
(whether CEPA “toxic”). Ministers were also required to respond (within 90 days) to
public nominations for additions to the List. If a report of an assessment was not
published within 5 years of the substance being added to the List, establishment of a
Board of Review could be requested under the Act. A summary of each assessment
was to be published in the Canada Gazette along with an indication of whether
Ministers intended to recommend the development of regulations to control the
Two lists of Priority Substances (PSL 1 and PSL 2) were generated prior to
the introduction of CEPA-1999. The first Priority Substances List, published in
February 1989, comprised 44 substances. A second list comprising 25 substances
was published in December, 1995. Both lists included classes of substances and
complex mixtures as well as discrete industrial chemicals. They were developed by
Panels of experts (Ministers’ Expert Advisory Panels) drawn from stakeholders and
convened under the authority of the Act. Annexes 1 and 2 list these priority
As described below (Section 4.1), assessment of the health and
environmental risks of priority substances entailed a comprehensive and scientifically
rigorous approach to decision making. Examination of the 69 listed priority
“substances” resulted in assessment of far more than this number in terms of
discrete chemical entities because of the complex nature of some of the entries (i.e.,
RISK ASSESSMENT OF CHEMICALS
mixtures and classes). Nevertheless, public expectation to consider the potential
health and the environment impacts of all 22,400 or so existing industrial chemicals
in Canada was increasing, a trend evident also in other parts of the world. This
expectation was reflected in the views of the Parliamentary Committee that reviewed
CEPA-88 and by the Commissioner on Environment and Sustainable Development
(CESD) . As a result, significant changes were made to the provisions for
existing substances in the renewed Act (CEPA-1999).
3.4 Categorization of the Domestic Substances List and screening
Figure 1. Existing Substances Program under CEPA-1999
CEPA-1999 incorporates a number of requirements to ensure that more
existing substances are assessed for health and environmental risks in shorter
timeframes, while at the same time retaining the PSL Assessment Program for
substances, mixtures or effluents deemed to require a more in-depth assessment.
Figure 1 depicts the processes for selecting and assessing existing substances. The
three principal phases of identification and assessment of priorities for risk
management specified under CEPA 1999 are categorization, screening assessment
and in-depth (Priority Substances List) assessment.
Substances identified as priorities from categorization or other selection
mechanisms must undergo screening risk assessments to determine whether they
are “toxic” or capable of becoming “toxic”. Another mechanism for triggering an
assessment of toxicity under CEPA-99 is the requirement to review decisions made
by other jurisdictions to prohibit or substantially restrict a substance for
environmental or health reasons. The requirement to establish a list of Priority
Substances, and the mechanism for doing so are retained under CEPA-1999.
Box 5.Substances were identified for further work if they met the following criteria:
may present, to individuals in Canada, the greatest potential for exposure; or
are persistent and/or bio-accumulative in accordance with regulations (see Section 5.1), and
are “inherently toxic” to human beings or non-human organisms. Note that in this context the
meaning of toxic is that in the generally accepted scientific sense, as determined by laboratory
or other studies.
Box 6. The possible outcomes of a screening level risk assessment, a risk assessment of a
Priority Substance, or a review of a decision made by another jurisdiction are that:
no further action be taken (typically if the substance is found not to be toxic);
a recommendation be made (to the federal Cabinet) that the substance be added to the List
of Toxic Substances with a view to developing to controls and, if applicable, be subject to
virtual elimination in order to adequately manage the risks to the environment or to human
the substance be added to the PSL for further review (if the substance is not already on the
The primary objective of screening and in-depth assessments is to determine
whether a substance is “CEPA-toxic” as defined under the Act, which may then set the
stage for addition of the substance to Schedule 1 (the List of Toxic Substances) of
the Act and for reviewing options for controlling risks to human health and/or the
3.5 Options for controlling existing substances
A wide range of regulatory instruments can be used under CEPA to control exposure
to substances deemed to be toxic with respect to any aspect of their lifecycle, from
the research and development stage to manufacture, use, storage and transport and,
ultimately, disposal. Regulations can address, for example, the amounts released to
the environment and where releases can occur, the conditions of release, quantities
manufactured or offered for sale in Canada, quantities imported, countries from, or
to, which a substances may be imported or exported, the manner in, and conditions
under, which a substance is advertised or offered for sale, how it is to be handled,
stored and transported.
RISK ASSESSMENT OF CHEMICALS
Figure 2. Regulatory Publication Process
Provisions also allow for the partial or total prohibition of manufacture, import or
export, and for the submission of information on the substance, the conduct of
analyses and monitoring and of tests, submission of samples to the government and
the maintenance of records. Before any such regulations are made, it must be
ascertained that a regulation does not address an aspect already effectively regulated
under another Act (See Section 2.1).
Controls can also take the form of guidelines, standards, codes of practice,
plans and voluntary or non-regulatory initiatives and may include any other
measures deemed appropriate based on the known level of risk, available
technology, and socio-economic considerations. The Act states that, in developing the
regulations or other control options, priority is to be given to pollution prevention
For substances that are “categorized in” and for which subsequent screening
assessment indicates that they are “toxic” to human health and/or the environment,
addition to the List of Toxic Substances requires that a proposed regulation or other
control instrument respecting preventative or control actions in relation to the
substances be published in the Canada Gazette within two years of the additions.
Final regulations or instruments must normally be developed and published in the
Canada Gazette within 18 months following the proposal. Figure 2 is a schematic
representation of the steps involved in developing control measures for toxic
When a substance is deemed to be “toxic” under CEPA and also meets certain criteria
for persistence and bioaccumulation, is not a naturally occurring radionuclide or
naturally occurring inorganic substance, and its presence in the environment results
primarily from human activity, ,the substance is then proposed for virtual elimination
under the Act.
Box 7. Risk management tools that can be considered in identifying options for managing
toxic substances under CEPA, 1999 are :
Regulations, pollution prevention plans, environmental emergency plans, administrative
agreements, codes of practice, environmental quality objectives or guidelines, release
Voluntary approaches - Environmental Performance Agreements, Memoranda of Understanding;
Non-CEPA 1999 economic instruments - financial incentives and subsidies, environmental
charges and taxes
Joint federal/provincial/territorial initiatives - Canada-wide Standards, guidelines, codes of
Provincial/territorial Acts - regulations, permits, or other processes;
Other federal Acts - e.g., Fisheries Act, Pest Control Products Act, Hazardous Products Act.
Virtual elimination (provisions for persistent, bioaccumulative, toxic
RISK ASSESSMENT OF CHEMICALS
Box 8. Definition of virtual elimination
Virtual elimination is “the ultimate reduction of the quantity or concentration of the substance in the
release below the level of quantitation specified by the Ministers in the (virtual elimination) List".
A Virtual Elimination List (the “List”) specifies the level of quantitation for
each substance included in the List. Virtual elimination would generally be achieved
through a series of progressive release limits set by regulations and/or other risk
3.7 Significant New Activities
Provisions for dealing with significant new activities with respect to chemical and
biotechnological substances were introduced in CEPA-1999; these provisions address
any new activity that results in, or may result in, significantly greater quantities or
concentrations of a substance in the environment, or a significantly different manner
or circumstances of exposure to a substance. They are intended to provide
additional flexibility and refinement in the application of both the new and existing
substances provisions by triggering re-notification of the substance under certain
The significant new activity (SNAc) provisions can be used to require a re-
notification of a new substance. A SNAc Notice may be issued defining what
constitutes a significant new activity in relation to the substance, by inclusion or
exclusion. The criteria under which a notification is required and information
requirements are also specified therein. This information is further assessed prior to
the commencement of any significant new activity to allow the substance to be
imported, manufactured, used or released in ways that would not pose a risk to the
environment and/or human life or health.
Significant New Activity Notifications (SNANs) contain all prescribed
information specified in the SNAc Notice and must be provided within the prescribed
time and prior to a company undertaking the significant new activity. Assessment of
the information must be completed within the prescribed assessment period .
A new substance subject to an SNAc Notice can be added to the DSL with a
SNAc (“S”) flag; this allows any individual to manufacture, import, use and release
the substance in ways that are not defined as a “new activity” under the terms of the
definition of ‘significant new activity’.
For existing substances, if an activity can be reasonably anticipated which
could substantially change the exposure and consequently the risk posed to the
environment and/or human life or health, an amendment to the DSL can be
published in the Canada Gazette. This amendment would include publishing a SNAc
Notice and placing a SNAc (“S”) flag on the substance. This again allows any
individual to manufacture, import, use and release the substance in ways that are not
defined as a “new activity” under the terms of the SNAc Notice.
3.8 Information gathering
Provisions for gathering and generating information required for the assessment or
control of existing substances under the Toxic Substances provisions of CEPA include
ones to ascertain who is using the substance, and to furnish the government with
any existing information (e.g., toxicological information, monitoring data, uses,
quantities in use) or samples and to conduct toxicological or other tests. Powers to
require industry to carry out testing or studies cannot be invoked unless there is
“reason to suspect that the substance is toxic or capable of becoming toxic or it has
been determined under this Act that the substance is toxic or capable of becoming
toxic”. Also a user, manufacturer or importer of a substance is required to provide to
the government any information that supports the conclusion that the substance is
toxic or capable of becoming toxic.
3.9 Consultation and communication
The results of an assessment of an existing substance (i.e., screening, PSL) or a
review of a decision made by another jurisdiction must be made public by issuing a
notice in the Canada Gazette. The notice must indicate whether no further action is
to be taken or whether the substance is to be added to the List of Priority Substances
(for further assessment) or to the List of Toxic Substances. A 60 day comment period
follows the issuing of these proposals. Provisions exist for objections to be raised if
no recommendations are made to add a Priority Substance to the List of Toxic
Substances; establishment of a Board of Review may be requested to review the
assessment conclusions. If it is proposed that a substance be added Schedule 1 (the
Toxic Substances List), consultation with the public is required through the
publication of a Notice in the Canada Gazette.
Control instruments are developed through consultations with stakeholders,
including industry and industry associations, non-governmental organisations (e.g.
environment, health and labour), provincial governments, economists, enforcement
officials and legal services. Provincial and territorial governments may be involved in
developing and implementing the options. All actions regarding toxic substances
should be consistent with the Toxic Substances Management Policy  (see also
4 HEALTH ASSESSMENTS UNDER CEPA
This section includes a brief description of the approaches used to implement the key
health-related components of the toxic substances provisions of CEPA-1999, with
emphasis on novel methodologies developed to address progressive and precedent-
setting requirements of the legislative mandate for Existing Substances (See
references listed under Section 8 for information relevant to assessment of New
Central to the evaluation of Existing Substances are two types of
assessments, namely screening and in depth (PSL). Differences and similarities
between these two types of health assessments are presented in Annex 3.
The provisions of CEPA-1999 for selecting (categorization being the most
significant), assessing (screening and in-depth) and managing the risks of existing
chemical substances, as depicted in Figure 1, are consistent with the principles
outlined in Health Canada’s “Decision-Making Framework for Identifying, Assessing,
and Managing Health Risks” .
RISK ASSESSMENT OF CHEMICALS
Figure 3. Phases in identifying and assessing health priorities
4.1 Comprehensive framework for health risk assessments under CEPA-
The objective of the health-related components of DSL categorization is the
identification, for additional consideration in screening, of substances that are highest
priorities in relation to their potential to cause adverse effects on the general
population. Figure 3 illustrates the steps (Phases) involved in identifying and
assessing health priorities in an integrated and iterative framework for priority setting
and assessment. To maximize efficiency, the complexity of priority setting, the
assessment and associated documentation is tailored to invest only that amount of
effort required to identify non-priorities while, at the same time, ensuring that the
assessment provides essential support for undertaking risk management of
substances where this is deemed to be required.
Phase 1: Tools-based priority-setting (categorization) and assessment
An element of the categorization mandate relevant to human health was the
identification of substances that present the greatest potential for the exposure of the
general population of Canada (GPE). Additionally, substances considered inherently
toxic to humans (iT-
persistent or bio-
criteria for which are
specified in regu-
lations under CEPA),
were to be identified.
In order to
identify true health
priorities, however, a
both exposure and
hazard for all
consideration of the criterion “inherently toxic to humans” to the subset of
substances considered to be persistent or bioaccumulative. This required multiple
stages of increasing complexity, involving development and application of simple and
complex exposure and hazard tools.
The simple exposure tool (SimET) was developed to accommodate
information submitted during the compilation of the DSL and has three lines of
quantity in commerce in Canada;
number of companies involved in commercial activities in Canada; and
weighting by experts of the potential for human exposure based on
consideration of various use codes.
Based on collective consideration of these three components, it was possible
to relatively rank all substances in relation to their potential for exposure. Based on
application of specific criteria for each of the components, all substances on the DSL
were grouped into one of three categories, i.e., those presenting “greatest”,
“intermediate” or “lowest” potential for exposure (GPE, IPE or LPE). The results of
relative ranking on this basis indicated that volume is not a good surrogate for
exposure with many of the highest volume substances presenting “lowest potential
Simple (SimHaz) and complex hazard tools (ComHaz) as well as a complex
exposure tool (ComET) were and continue to be developed and implemented within
an integrated framework for the health-related components of DSL categorization.
The complex tools contribute considerably to predictive methodology for both
exposure and hazard, including the development of significant numbers of additional
• SimET (Relative ranking of all DSL substances based on submitters (S),quantity (Q)
and expert ranked use (ERU))
• ComET (Quantitative plausible maximum age-specific estimates of environmental and
consumer exposure for individuals based on use scenario (sentinel products),
physical/chemical properties & bioavailability)
Hazard [High (H) or Low (L)]
• SimHaz (Identification of high or low hazard compounds by various agencies based
on weight of evidence for multiple endpoints)
• ComHaz (Hierarchical approach for multiple endpoints & data sources (e.g.,
quantitative-structure activity relationships) including weight of evidence)
Tools for Health-Related Components of DSL Categorization
RISK ASSESSMENT OF CHEMICALS
consumer exposure scenarios and a systematic weight of evidence approach to take
into account data, results of a suite of quantitative structure activity analysis models
and analogue approaches.(For additional information on the tools see http://www.hc-
Figure 4. Tools-based approach for health-related components of DSL categorization
The simple exposure and hazard tools were applied to the entire DSL leading
to a draft “maximal list” of health priorities, released in October, 2004 . The
potential for persistence or bioaccumulation to additionally contribute to exposure for
certain subsets of substances, namely, those that are organic, was also taken into
account (Figure 4).
This approach offered a number of advantages and exceeded the
requirements of categorization, by:
drawing maximally on work completed in other jurisdictions while avoiding
continued focus on data-rich compounds;
not only identifying substances for screening assessment on the basis of
exposure, hazard, and/or risk, but also prioritizing them on the basis of potential
exposure, hazard, and/or risk to human health;
identifying true priorities for both assessment and data generation, since
exposure and complex hazard components of the framework were unbiased in
relation to data availability; and
identifying not only those substances that were iT-human for a subset of
substances, but all of the approximately 22 400 existing substances based on
criteria for weight of evidence of hazard consistent with those for Priority
Substances or screening health assessment.
Implementation of this framework and associated tools has application well
beyond simply identifying substances for assessment. These tools enable the efficient
prioritization and subsequent screening health assessment of any substance
considered by the program. Health priorities from categorization have been
prioritized by group, based on whether they are exposure, hazard, or risk based, and
within groups, based on consideration of their relative potential for exposure.
Continued application of the complex tools additionally focused the content of the
results of categorization and will contribute to screening assessment for prioritized
The development of the tools and related products for categorization drew
upon considerable prior program experience gained in developing the methodology
for conducting in-depth, detailed human health risk assessments of the 69 “Priority
Substances,”; most of these assessments were published in the peer-reviewed
scientific literature and/or served as the basis for international criteria documents
Substances considered as health priorities based on application of the simple
tools are addressed in Phase II, Issue Identification.
Phase II: Issue identification
To increase the efficiency in assessment, it is envisaged that screening health
assessments for Existing Substances will incorporate an early stage of Issue
Identification. The objective is to ensure timely and maximum utilization of
previously well documented peer reviewed assessments and adequate and accurate
focus on more recent information and critical issues. While the process for input and
content are still in development, robust senior internal technical review and external
peer input would be critical to ensure integrity of the product. Formats for
supporting use and toxicity profiles have been developed and draw maximally on
available information, based on comprehensive and well documented search
strategies and solicitation for submission of relevant information.
This stage provides risk managers and stakeholders with the opportunity to
contribute information, for example, in the preparation of use and exposure profiles
(i.e., identification of specific end uses and potential for exposure); it also provides
early indication of potential focus of the assessment and (possible) subsequent risk
Phase III: (Focussed) screening assessments
The objective of a screening health assessment is, to efficiently consider whether or
not a substance poses a risk to human health. To increase efficiency, the focus of
the assessment is limited principally to information which is considered most critical
RISK ASSESSMENT OF CHEMICALS
with respect to exposure to, and health-related effects of, a substance, in particular
the critical aspects identified during Issue Identification. Substances are assessed
only to the extent necessary to deem them to be non-priorities, or to provide
necessary guidance as a basis for risk management. Depending upon complexity of
the issues, complexity of process for peer input may increase (e.g., more of the
nature of that for Priority Substances). The objective is to maintain scientific rigour,
depending, for example, on the priority for health effects evaluation (based on
application of the simple tools) and on the extent of the database, but to vary the
degree of detail (and hence the level of effort for the assessment).
Focussed screening health assessments result in the issue of a State of the
Science Report which undergoes internal and external peer review and is posted on
the web and/or sent to stakeholders. The state of the science report presents only
the technical and scientific information on a substance or a group of substances and
serves to provide an early indication of the basis for forthcoming conclusions and
recommendations; the conclusion of whether or not a substance is “toxic” under the
Act and any proposed Ministerial recommendations are published in the Canada
Gazette which also serves to link the health and environmental assessments.
With respect to the health of the general public, it is the potential for adverse
effects following long-term exposure to the, generally, low environmental levels that
is often of importance as a basis for decision making (that is, to set a substance
aside with no further action, add it to the Priority Substances List, or to recommend
addition to the List of Toxic Substances). Hazard characterization for both screening
and in-depth (PSL) health assessments entail an examination of the effects critical to
adults’ and children’s health, such as potential organ-specific effects or more
specialized hazards such as immunotoxicity, neurological/behavioural toxicity,
reproductive toxicity, genotoxicity, cancer and developmental effects. Exposure
analyses include consideration of all relevant media and are based on six different
age groups (an example is provided in Table 2).
Decision-making for screening health assessments is based on analysis of a
margin of exposure (MOE), that is, comparison of critical effect levels with estimates
of exposure taking into account the confidence/uncertainties in the available
exposure and toxicological databases and other relevant data (e.g., ancillary data on
toxicokinetics and/or mode of action). This ensures maximal utilization of available
data with several MOEs for potentially critical effects and studies being considered
along with associated uncertainties. Delineation of the relative uncertainty and
degree of confidence in the exposure and effects databases forms, therefore, a
central component of the documentation for screening (and PSL) health assessments.
For example, the adequacy of the margin for human health protection takes into
account whether exposures are based upon only modelling, measured concentrations
of a substance in media important to estimating human exposure (i.e., air,
foodstuffs, drinking water, soil, consumer products) or human biomonitoring studies
that provide a measure of actual human exposure. It also takes into account the
extent of the database as the basis for characterization of hazard and dose-response
for all effects particularly those considered critical, including degree of conservatism
in the selection of the critical effect. Reliance on MOEs rather than TDIs in screening
assessments contributes additionally to efficiency of the process by enabling
assessment of larger numbers of substances, drawing maximally on the available
database, while minimizing the need for development of exposure-based guidance
values for substances that are not considered priorities for further action.
Table 2. Upper-bounding estimates of daily intake of 1,2-dibromoethane (From
reference 28; citations in footnotes are as given therein)
Estimated intake (µg/kg-bw per day) of 1,2-dibromoethane by various
Ambient air9 0.0050
Indoor air10 0.0044
Drinking water11 0.0016
Soil13 1.6 × 10-5 2.6 × 10-5 8.4 × 10-6 2.0 × 10-6 1.7 × 10-6 1.7 × 10-6
Total intake 0.014 0.089 0.080
No data were identified on concentrations of 1,2-dibromoethane in breast milk.
2 Assumed to weigh 7.5 kg, to breathe 2.1 m3 of air per day, to drink 0.8 L of water per day
(formula fed) or 0.3 L/day (not formula fed) and to ingest 30 mg of soil per day (EHD, 1998).
3 For exclusively formula-fed infants, intake from water is synonymous with intake from food. The
concentration of 1,2-dibromoethane in water used to reconstitute formula was based on data from
City of Toronto (1990). No data on concentrations of 1,2-dibromoethane in formula were identified
for Canada. Approximately 50% of non-formula-fed infants are introduced to solid foods by 4
months of age, and 90% by 6 months of age (NHW, 1990).
4 Assumed to weigh 15.5 kg, to breathe 9.3 m3 of air per day, to drink 0.7 L of water per day and to
ingest 100 mg of soil per day (EHD, 1998).
5 Assumed to weigh 31.0 kg, to breathe 14.5 m3 of air per day, to drink 1.1 L of water per day and
to ingest 65 mg of soil per day (EHD, 1998).
6 Assumed to weigh 59.4 kg, to breathe 15.8 m3 of air per day, to drink 1.2 L of water per day and
to ingest 30 mg of soil per day (EHD, 1998).
7 Assumed to weigh 70.9 kg, to breathe 16.2 m3 of air per day, to drink 1.5 L of water per day and
to ingest 30 mg of soil per day (EHD, 1998).
8 Assumed to weigh 72.0 kg, to breathe 14.3 m3 of air per day, to drink 1.6 L of water per day and
to ingest 30 mg of soil per day (EHD, 1998).
9 Based on the highest concentration (0.143 µg/m3) detected for 1,2-dibromoethane in 6766 of
8275 samples of ambient air collected in a national survey across Canada between 1998 and 2002
(Environment Canada, 2002). This survey was selected due to its expansiveness and its currency,
which will likely reflect declining use of 1,2-dibromoethane in Canada. Canadians are assumed to
spend 3 h per day outdoors (EHD, 1998). Data from which the critical data were selected included
Health Canada (2003), Environment Canada (1991, 1992, 1994, 1995 and 2001b), OMEE (1994)
and CMHC (1989).
In the absence of measured data, the detection limit (0.018 µg/m3) for a recent indoor air study of
75 homes in Ottawa, Ontario, was used (Health Canada, 2003b). Canadians are assumed to spend
21 h indoors every day (EHD, 1998). Data from which the critical data were selected included
Otson (1986), Cal. EPA (1992) and Cohen et al. (1989).
11 In the absence of measured data, the detection limit (0.04 µg/L) from 7 bottled and 27 tap water
samples in Toronto, Ontario, was used (City of Toronto, 1990). Data from which the critical data
were selected included OME (1988), OMEE (1993) and Golder Associates (1987).
12 In the absence of Canadian monitoring data, detection limits were used in the calculations. A
single 1,2-dibromoethane measurement of 13 µg/kg in sweet cucumber pickles in 1995 (U.S. FDA,
2003) was not considered, as the use of detection limits overcompensated its contribution to the
overall intake of vegetables in the calculations. In addition, older studies (Gunderson, 1988) in
which 1,2-dibromoethane was detected were not used to calculate intake levels, as pesticidal use
of 1,2-dibromoethane at that time likely led to levels in food that would not be representative
Route of exposure
8.0 × 10-4 8.0 × 10-4 9.0 × 10-4
0.058 0.037 0.022 0.020 0.016
0.054 0.032 0.028 0.024
RISK ASSESSMENT OF CHEMICALS
- Dairy products
- Cereal products
- Meat & poultry
- Foods, primarily sugar
- Mixed dishes & soups
- Nuts & seeds
- Soft drinks & alcohol
Amounts of foods consumed on a daily basis by each age group are described by Health Canada
The method detection limit (4.0 ng/g) for soil measurements in urban (59 samples) and rural (102
samples) parklands in Ontario was used to represent the maximum exposure concentration of 1,2-
dibromoethane (OMEE, 1993). Data from which the critical data were selected included Golder
Where relevant and available, toxicokinetic data and weight of evidence for
hypothesized modes of action and human relevance are taken into account in
transparent analytical frameworks [29, 30]. An example of a margin of exposure
analysis which appears in the State of the Science report on “perfluorooctane
sulphonate (PFOS), its salts and precursors containing the C8F17SO3 moiety” is
presented in Table 3.
Decisions on the adequacy of margins take into account the experience
gained through conducting screening assessment of large numbers of chemicals and
considering the adequacy of various margins for human health protection for
chemical substances with a wide variety of datasets. The approach by which these
factors are considered in decision-making for screening health assessment has been
built upon the experience gained, and are consistent with, decision-making in the
health risk assessment of Priority Substances. Weight of evidence for effects for
which available data on mode of action indicate that there is a probability of harm at
all levels of exposure is also considered in decision-making.
Where it is ascertained from a screening assessment that a more
comprehensive analysis of available data (e.g., a complex analysis of exposures from
consumer products) and/or the generation of additional data (e.g., on mode of
action) is warranted to more fully inform decision-making in order to reach a
definitive conclusion, more detailed assessments are undertaken.
An option stipulated in CEPA-1999 is to recommend that a substance be
added to the PSL. Any recommendation for this action would necessitate defining
what needs to be done to further develop the assessment (e.g., request additional
information from industry to be able to better assess exposure, examine mode of
action) and ascertaining whether such a course would be more advantageous to the
Table 3. Margins of exposure for PFOS (From reference 31; citations in footnotes are
as given therein)
and effect metric at
PFOS dose Metric(s) of human exposure to
Mean serum PFOS level in
adults in Canada3:
95th percentile of human serum
PFOS level in adults in Canada3:
Mean serum PFOS level in
children in the United States4:
95th percentile of serum PFOS
level in children in the United
Mean6 liver PFOS level:
changes in the
liver of rats (m +
f) receiving PFOS
in the diet for 2
Mean serum PFOS level in
adults in Canada3:
95th percentile of human serum
PFOS level in adults in Canada3:
Mean serum PFOS level in
children in the United States4:
95th percentile of serum PFOS
level in children in the United
Mean10 liver PFOS level:
(m) and total
bilirubin (m) in
PFOS for 26
Covenance Laboratories, Inc. (2002a)
Average of mean levels in males (7.6 µg/mL) and females (20.2 µg/mL).
Kubwabo et al. (2002)
3M Medical Department (2002)
Average of mean levels in males 26.4 (µg/g) and females (55.1 µg/g).
Mean level of PFOS in livers from 30 cadavers (Olsen et al., 2003).
Published data on 95th percentile not available; margin of exposure based upon highest level of
PFOS in human liver from this study (0.057 µg/g) is 716.
Average of mean levels in males (15.8 µg/mL and females (13.2 µg/mL) (week 26).
Average of mean levels in males 17.3 (µg/g) and females (22.2 µg/g) (week 27).
Mean level of PFOS in livers from 30 cadavers
Published data on 95th percentile not available. Margin of exposure based upon highest level of
PFOS in human liver from this study (0.057 µg/g) is 347.
RISK ASSESSMENT OF CHEMICALS
In view of the objective of CEPA1999 to assess much larger numbers of substances
more efficiently, the comprehensive and process intensive approach adopted for
Priority Substances will likely be confined to very limited numbers of compounds
and/or specific aspects of assessments on specific substances, which warrant a
complex process and content.
For substances on the first PSL (PSL 1), chemicals were classified formally
into discrete groups with respect to both their potential carcinogenicity and
mutagenicity in humans based on clearly defined criteria for weight of evidence which
took into account the quantity, quality and nature of the results of available
toxicological and epidemiological studies . For the assessment of PSL 2
substances (and more recent screening assessments), descriptions of the weight of
evidence for carcinogenicity are more narrative in nature, in the interest of
accommodating increasing availability of data on mode of action. To provide guidance
in setting priorities for managing the risks of substances considered to present a risk
of cancer and/or heritable mutations, Exposure was compared with the dose
associated with a specified (5%) increase in tumour incidence as a basis for
development of a measure of dose-response (i.e., Exposure/Potency Indices).
For some Priority Substances, the critical effect for decision-making was
considered to be associated with a mode of action for which where there is a dose or
exposure concentration below which adverse health effects are not likely to be
observed (i.e., organ specific toxicity and/or cancer associated with same). For these
substances, Tolerable Intakes or Tolerable Concentrations (TI or TC) (i.e., the intake
or concentration to which it is believed a person can be exposed daily over a lifetime
without deleterious effect), were derived by dividing the critical effect level (e.g.,
Benchmark Dose or Concentration (BMD or BMC) or No- or Lowest-Observed-
(Adverse)-Effect-Levels (NO(A)EL or LO(A)EL) by an uncertainty factor. The
Benchmark dose/concentration is the effective dose/concentrations (or their lower
confidence limits) that produce a specified increase in incidence above control levels.
The basis for uncertainty factors is clearly delineated and, where available data
permit, replaced by chemical-specific adjustment factors .
Details of the application of the above-mentioned approaches are available in
the assessment reports for the Priority Substances, all of which are available at
(See also Annex 3 for information on differences and similarities between screening
and PSL assessments).
Mixtures of substances
The approach for priority setting and/or assessing mixtures of chemicals depends on
the nature of data available . In some instances, the chemical composition of a
mixture may be well characterized, levels of exposure of the population known, and
detailed toxicological data on the mixture are available. More frequently, however,
not all components of the mixture are known, exposure data are uncertain and the
toxicological data are limited. Thus the approach that can be used will depend on
whether data are available:
for the mixture as a whole;
only for components of mixture;
for similar mixture(s).
4.5 Data requirements, information gathering and peer involvement.
Search strategies for all aspects of the program are comprehensive and documented
in the reports of various stages of priority setting (categorization), and assessment
(Issue identification, screening and PSL). For substances that are considered as
health priorities in screening, in most cases, there is no legislated minimum dataset;
however the Screening Information Dataset in the OECD High Production Volume
Chemicals Program , or equivalent, is considered an appropriate basis to
complete the assessments. Mechanisms for gathering information under CEPA are
described in Section 3.8. Experience acquired in use-profiling from public sources for
hundreds of chemicals based on hierarchical, evolving and comprehensive search
strategies as part of input for the complex exposure tool provides a consistent and
robust basis for understanding the use patterns of the vast majority of chemicals of
The conclusions and findings of an assessment, proposed and final regulations and
other proposed or final actions under CEPA must ultimately be announced in the
Canada Gazette. Reports of the outcome of screening assessments, assessments of
priority substances and reviews of other jurisdictions’ decisions can also be made
available “in any other manner that the Minister (of the Environment) considers
appropriate”. These announcements must state whether the Ministers intend to take
no further action respecting the substance, to add a substance to the PSL (unless it is
already on the List), or to recommend that the substance be added to the List of
The nature and scope of the documentation for the health assessments has
been modified with the change in emphasis from assessment of priority substances to
categorizing and screening substances on the DSL. Available reports include State of
the Science reports for screening assessments and their supporting documentation
(including Issue Identifications and use and hazard profiles), PSL assessment reports
and supporting documentation and briefer tabulations of output for non-priority tools
based assessments, with much more extensive documentation available on the
methodology. Considerable efficiency is gained in tailoring the level of
documentation to the task at hand, involving no more effort than is necessary to set
aside a substance as a non-priority or to provide necessary information to permit risk
management (see Figure 3).
Concise State of the Science reports of the screening health assessments
constitute an essential basis for documenting and communicating to the public the
scientific basis for the conclusions and decisions required under CEPA. The objective
is to produce as concise a document as possible containing only the critical (relevant)
information that supports the ultimate conclusion of whether a substance is “toxic”,
“suspected of being “toxic”, or “not considered to be toxic”, and the
decision/recommendation for any further action; thus the initial focus is on the most
RISK ASSESSMENT OF CHEMICALS
critical effects and conservative effect levels and upper-bounding estimates of
exposure. State of the Science reports are issued without the Ministerial conclusions
and recommendations as a means of alerting stakeholders to the scientific
underpinning upon which any recommendations will be based; these conclusions
appear subsequently in the Canada Gazette Notice along with a synopsis of the
technical findings. The State of the Science report and Conclusions in the Canada
Gazette represent the Screening Assessment Report under CEPA.
Critical information included in screening assessments comprises the
identity, production and uses of the substances, sources and levels of human
exposure, and health effects. The screening assessment report also outlines the
objective of the screening assessment, and delineates the databases which serve as
the basis for determining the critical effect levels and upper bounding exposure
estimates. For brevity, both hazard (health effects) and exposure (intake) data are
tabulated where possible. Screening assessment reports are made available following
external peer review and Departmental management approval of their content and of
the process followed in their preparation.
More detailed documentation supports the summarized technical data
presented in the assessment reports. For the PSL assessment program, the
supporting documentation comprised detailed text, multiple tables and a
comprehensive reference list; this documentation was designed to present and
describe in detail all relevant data needed to demonstrate how the critical exposure
and effects were determined. The textual content of the supporting documentation
was extensive and required investment of considerable time and resources.
In the interest of meeting objectives to more efficiently assess larger
numbers of substances, supporting documentation for the screening assessments is
much more issue-focussed and comprises a series of background documents and
data tabulations prepared during the course of an assessment rather than integration
into a comprehensive criteria document. The extent of this documentation is
necessarily dependent upon the tools-based designated priority of the substance and
complexity of the issues. For substances designated as priorities for assessment, it
includes, as a minimum, Issue Identifications, exposure and hazard profiles. Tabular
summaries of supporting information focussed in critical areas will also be included.
These may include survey results, exposure scenarios, robust data summaries for
critical studies, framework analyses for weight of evidence of specific endpoints
(cancer/genotoxicity), and hypothesized modes of action and relevance to humans.
For “tools-based” assessments the results of which indicate non-priorities for
additional work, supporting documentation is limited principally to the more
extensive documentation on methodology
with some chemical-specific information available on request (e.g., weight of
evidence for cancer/genotoxicity based on data, quantitative structure activity
analyses and consideration of analogues). For such substances, State of the Science
reports and Gazette Notices report conclusions on significant numbers of substances
in tabular format.
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Because of CEPA’s requirement to set priorities from thousands of existing chemicals
and the associated need to develop novel methodologies and the expectation for
rapid review of prioritized substances, the program provides opportunity for
incorporation of increasingly complex peer involvement not, only in the assessments
of individual or groups of substances, but also in the development of novel
methodology for categorization.
Specifically, the program has incorporated to an increasing extent more
formal peer input at the earlier stages of development for both methodology and
assessments. In addition, the complexity of peer input, consultation, and peer
review is greater for more robust assessments for substances of highest priority and
complex issues such as methodology development. This approach maximizes
efficiency while maintaining the defensibility of output of the three different levels of
priority setting and assessments of increasing complexity within the program
(categorization, screening assessment, and full assessment).
Table 4 Peer involvement for each stage of product development.
Draft Work Product
Final Draft Work Product
The three types of peer involvement, the level and complexity of which
increases with the stage of development of documentation and complexity of issues
as discussed by Meek et al.  and their utilization in various stages of the program
are presented in Table 4
Full assessments for Priority Substances generally include early peer input to
identify relevant data followed by external panel peer reviews at the end of the
process. On the other hand, for screening assessments, there is an early issue
identification stage to solicit peer input on identification of relevant data and issues
and confirming the focus of the assessment. Since screening assessments are less
complex, at a later stage in their development, their peer review is generally
restricted to written comments by several external experts. Panel meetings are
convened only where there are subsequent outstanding issues. Development of
methodology for priority setting and/or assessment of risk often entails all three
stages of peer involvement (i.e., input, consultation and review).