Animal carcinogenicity studies: 1. Poor human predictivity.
ABSTRACT The regulation of human exposure to potentially carcinogenic chemicals constitutes society's most important use of animal carcinogenicity data. Environmental contaminants of greatest concern within the USA are listed in the Environmental Protection Agency's (EPA's) Integrated Risk Information System (IRIS) chemicals database. However, of the 160 IRIS chemicals lacking even limited human exposure data but possessing animal data that had received a human carcinogenicity assessment by 1 January 2004, we found that in most cases (58.1%; 93/160), the EPA considered animal carcinogenicity data inadequate to support a classification of probable human carcinogen or non-carcinogen. For the 128 chemicals with human or animal data also assessed by the World Health Organisation's International Agency for Research on Cancer (IARC), human carcinogenicity classifications were compatible with EPA classifications only for those 17 having at least limited human data (p = 0.5896). For those 111 primarily reliant on animal data, the EPA was much more likely than the IARC to assign carcinogenicity classifications indicative of greater human risk (p < 0.0001). The IARC is a leading international authority on carcinogenicity assessments, and its significantly different human carcinogenicity classifications of identical chemicals indicate that: 1) in the absence of significant human data, the EPA is over-reliant on animal carcinogenicity data; 2) as a result, the EPA tends to over-predict carcinogenic risk; and 3) the true predictivity for human carcinogenicity of animal data is even poorer than is indicated by EPA figures alone. The EPA policy of erroneously assuming that tumours in animals are indicative of human carcinogenicity is implicated as a primary cause of these errors.
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Since the first chemical bioassay occurred in 1915,
when Yamagiwa and Ichikawa showed that coal tar
applied to rabbit ears caused skin carcinomas (1),
several thousand have been conducted, with the
objective of determining the risks posed to humans
by the great majority of chemicals for which ade-
quate human exposure data are lacking. However,
despite the heavy reliance of governmental regula-
tory agencies on animal carcinogenicity testing, this
remains a controversial area of animal research.
Proponents of the bioassay claim that all known
human carcinogens that have been studied in suffi-
cient animal species have produced positive results
in one or more species (2–4). Critics respond that, if
sufficient animal testing is conducted, carcinogene-
sis will eventually occur in some species, regardless
of the cancer risk from a particular chemical. A
study published in the journal, Mutagenesis, found
that of 20 known human non-carcinogens, 19 were
known animal carcinogens (5). Other investigators
have also reported the poor human specificity (the
ability to identify human non-carcinogens) of car-
cinogenicity bioassays, and have noted the consid-
erable biological and mathematical complexities of
attempting to accurately extrapolate animal car-
cinogenicity data to humans (6–8).
Other key disadvantages of animal carcinogenic-
ity studies are their protracted time-frames, and
their substantial demands on human, animal and
financial resources. Monro and MacDonald (9) esti-
mated that rodent bioassays take at least three
years to plan, execute and interpret. Millions of
skilled personnel hours have been consumed in
these studies to date.
Ashby (10) estimated that the bioassay evalua-
tions of 400 chemicals by the US National
Toxicology Program (NTP) from the 1970s to the
1990s cost hundreds of millions of dollars. As of
2005, the bioassay results of 6153 experiments on
1485 chemicals were included in the comprehensive
Berkeley-based carcinogenic potency database
(CPDB; 11). Greek and Greek (12) estimated that
the cost of carcinogenicity bioassays exceeds 250
million dollars annually.
Similarly, millions of animal lives have been con-
sumed by animal carcinogenicity studies. Monro
Animal Carcinogenicity Studies: 1. Poor Human
Andrew Knight,1Jarrod Bailey2and Jonathan Balcombe3
1Animal Consultants International, London, UK; 2School of Population and Health Sciences, Faculty of
Medical Sciences, University of Newcastle upon Tyne, Newcastle upon Tyne, UK; 3Physicians Committee for
Responsible Medicine, Washington DC, USA
Summary — The regulation of human exposure to potentially carcinogenic chemicals constitutes society’s
most important use of animal carcinogenicity data. Environmental contaminants of greatest concern within
the USA are listed in the Environmental Protection Agency’s (EPA’s) Integrated Risk Information System (IRIS)
chemicals database. However, of the 160 IRIS chemicals lacking even limited human exposure data but pos-
sessing animal data that had received a human carcinogenicity assessment by 1 January 2004, we found that
in most cases (58.1%; 93/160), the EPA considered animal carcinogenicity data inadequate to support a clas-
sification of probable human carcinogen or non-carcinogen. For the 128 chemicals with human or animal
data also assessed by the World Health Organisation’s International Agency for Research on Cancer (IARC),
human carcinogenicity classifications were compatible with EPA classifications only for those 17 having at
least limited human data (p = 0.5896). For those 111 primarily reliant on animal data, the EPA was much
more likely than the IARC to assign carcinogenicity classifications indicative of greater human risk
(p < 0.0001). The IARC is a leading international authority on carcinogenicity assessments, and its signifi-
cantly different human carcinogenicity classifications of identical chemicals indicate that: 1) in the absence of
significant human data, the EPA is over-reliant on animal carcinogenicity data; 2) as a result, the EPA tends
to over-predict carcinogenic risk; and 3) the true predictivity for human carcinogenicity of animal data is even
poorer than is indicated by EPA figures alone. The EPA policy of erroneously assuming that tumours in ani-
mals are indicative of human carcinogenicity is implicated as a primary cause of these errors.
Key words: animal experiment, animal test, bioassay, cancer prevention, carcinogenicity, chemical
classification, chemical safety, risk assessment.
Address for correspondence: A. Knight, Animal Consultants International, 91 Vanbrugh Court, Wincott
Street, London SE11 4NR, UK.
ATLA 34, 19–27, 2006 19
and MacDonald (9) estimated that a single carcino-
genicity bioassay may use over 1200 animals.
Furthermore, data from the USA (13) and Canada
(14) indicate that testing procedures such as car-
cinogenicity studies, account for most of the ani-
mals that are reported as experiencing the highest
levels of pain and distress in laboratory studies.
That pain and distress is not short-term. As exem-
plified by the US National Cancer Institute/
National Toxicology Program (NCI/NTP) protocol,
dosing in the standard rodent bioassay begins at six
to eight weeks of age and continues for 90 to 110
weeks, a period similar to the natural rodent lifes-
pan, after which any remaining survivors are killed
and autopsied (15).
In 2004, Pound et al. (16) pointed out in the
British Medical Journal that justifications for the
use of animal tests in safeguarding human health
have sometimes relied on anecdotal evidence or
unsupported claims. Given increasing concern
about the ethical issues posed by animal testing,
and increasing competition for scarce research
resources, critical reviews of the value of animal
tests in safeguarding human health are clearly war-
Consequently, we have systematically reviewed
the human utility of animal carcinogenicity data
for regulatory purposes. The control of human
exposure to various potential carcinogens consti-
tutes the most important use of animal carcino-
genicity data. The US federal agency most
responsible for regulating exposure to potentially
dangerous environmental contaminants is the
Environmental Protection Agency (EPA; 17), and
the chemicals of greatest concern within the USA
(18) are listed in the EPA’s Integrated Risk
Information System (IRIS) chemicals database,
along with their toxicity data and human carcino-
genicity assessments (19).
To assess the reliability of EPA carcinogenicity
assessments, we compared them with those of
the World Health Organisation’s International
Agency for Research on Cancer (IARC), as pub-
lished in its IARC Monographs Programme on
the Evaluation of Carcinogenic Risks to Humans.
Compiled by international working groups of sci-
entific experts, the IARC Monographs provide
critical reviews and evaluations of the evidence
relating to the possible carcinogenicity of a wide
variety of agents, mixtures and exposures. They
are recognised as authoritative sources of infor-
mation, and assist governmental agencies in
making risk assessments and in formulating
decisions concerning any necessary preventive
measures. A 1998 users’ survey indicated that
the IARC Monographs are consulted by various
agencies in 57 countries — 4000 copies of each
volume are usually printed, for distribution to
governments, regulatory bodies and interested
We examined the 543 chemicals catalogued in the
EPA’s IRIS chemicals database (as of 1 January
2004; 21) to determine the proportion for which the
EPA was able to derive classifications of probable
human carcinogen or probable human non-carcino-
gen, based primarily on animal carcinogenicity data.
The relatively few classifications of definite human
carcinogen relied primarily on available human
exposure data. The remaining classifications of
unclassifiable or possible human carcinogen were
not considered substantially useful for risk assess-
ment or regulatory purposes, and are excluded from
the NTP’s authoritative annual Report on Carcin-
Of the 235 chemicals assigned human carcino-
genicity classifications by the EPA, we determined
the proportion in each of the following categories,
along with the reason for the classification:
— A: Human Carcinogen (convincing evidence of
— B1: Probable Human Carcinogen (limited evi-
dence of human carcinogenicity).
— B2: Probable Human Carcinogen (sufficient evi-
dence of animal carcinogenicity).
— C: Possible Human Carcinogen (animal data
inadequate for stronger classification).
— D: Unclassifiable (animal data inadequate for
— D: Unclassifiable (no animal or human data).
— E: Evidence of Non-Carcinogenicity for Humans
(sufficient evidence of non-carcinogenicity, at
least in animals).
The 160 chemicals lacking even limited human car-
cinogenicity data but possessing animal carcino-
genicity data, were then examined, to determine
the proportion for which the EPA considered the
animal data strong enough to assign the classifica-
tions of probable human carcinogen (B2) or proba-
ble human non-carcinogen (E). A 95% confidence
interval for this proportion was derived via the
modified Wald method, which is described in The
American Statistician as providing more accurate
results than the so-called “exact” method com-
monly used (23).
To compare EPA carcinogenicity classifications
with those assigned by the IARC, we examined the
885 agents (chemicals, groups of chemicals, com-
plex mixtures, occupational exposures, cultural
habits, biological or physical agents) assigned
human carcinogenicity classifications in the first 82
volumes of the IARC Monographs series published
by 1 January 2004. We determined the proportion
in each of the following IARC categories:
— 1: Human Carcinogen.
20 A. Knight et al.
Poor predictivity of carcinogenicity studies 21
— 2A: Probable Human Carcinogen.
— 2B: Possible Human Carcinogen.
— 3: Human Carcinogenicity Unclassifiable.
— 4: Probable Human Non-Carcinogen.
Like the EPA, the IARC classified definite human
carcinogens on the basis of convincing human data,
and probable human non-carcinogens on at least
sufficient animal data. Unlike the EPA, however,
the IARC did not subdivide probable human car-
cinogens into those based on limited evidence of
human carcinogenicity and those based solely on
animal carcinogenicity data. This prevented calcu-
lation of the proportion of agents classified by the
IARC as probable human carcinogens primarily on
the basis of their animal carcinogenicity data, other
than by examination of a large number of IARC
agents individually, an approach which we did not
undertake. This is one of the reasons we chose
instead to use EPA classifications to derive our ini-
tial assessments of the human utility of animal car-
Of the 177 chemicals that had received a human
carcinogenicity classification from the EPA based
on human or animal data, 128 were assigned
human carcinogenicity classifications by both the
EPA and the IARC. These 128 were divided into
those considered by the EPA to possess at least lim-
ited human data (17 chemicals) and those primarily
reliant on animal data (111 chemicals) for their
human carcinogenicity classifications.
The consistency of classifications between the
EPA and IARC was examined for these two groups,
by comparing the carcinogenicity classification pro-
portions within each group via chi-squared tests,
and by comparing the individual classifications of
the 111 chemicals primarily reliant on animal car-
cinogenicity data for their human carcinogenicity
Chi-squared tests provide a statistical calculation
of the probability that two data sets, such as the
EPA and IARC human carcinogenicity classifica-
tions, are samples from the same underlying data
population, and that any observed differences are
simply due to random sampling variation. Large
chi-squared values (χ2) reflect increased probabili-
ties that observed differences are due to real differ-
ences in underlying data populations.
Chi-squared and two-tailed p values were derived
from the online statistical calculators available at
EPA and IARC human carcinogenicity
Of the 543 chemicals catalogued in the EPA’s IRIS
chemicals database, 235 had been assigned human
carcinogenicity classifications. Of these, 17 were
classified as definite (A) or probable (B1) human
carcinogens on the basis of their human carcino-
genicity data. Of the remaining 218 chemicals lack-
ing even limited human data, 160 were deemed to
possess animal carcinogenicity data (B2, C, subset
of D, and E; Table 1).
Table 2 lists the IARC human carcinogenicity
classifications of the 885 agents described in the
first 82 volumes of the IARC Monographs series. As
stated, the IARC also classified definite human car-
cinogens (category 1) on the basis of convincing
human data, and probable human non-carcinogens
(category 4) required at least sufficient animal data.
Unlike the EPA classifications of B1 and B2, how-
ever, the IARC did not subdivide probable human
carcinogens (2A) into those based on limited evi-
dence of human carcinogenicity, and those based
solely on animal carcinogenicity data.
Table 1: EPA human carcinogenicity classifications of IRIS chemicals
chemicals EPA human carcinogenicity classification% of total
B1: Probable Human Carcinogen (limited human data)
B2: Probable Human Carcinogen (sufficient animal or human data)
C: Possible Human Carcinogen (animal data inadequate for stronger classification)
D:Unclassifiable (animal data inadequate for stronger classification)
D:Unclassifiable (no animal or human data)
E:Probable Human Non-Carcinogen (sufficient animal data)
Human Carcinogen (convincing human data) 114.7
160 chemicals lacking in human data had received a human carcinogenicity assessment primarily on the basis of their
animal data. Data source: EPA Integrated Risk Information System database, 1 January 2004.
The human utility of animal carcinogenicity
data based on EPA figures
Of the 160 EPA chemicals lacking even limited
human data (A or B1) but possessing animal data
(B2, C, subset of D, and E), 64 were considered
probable human carcinogens (B2), and three were
considered probably not carcinogenic to humans
(E). For those considered probably not carcino-
genic to humans, in some cases, data arising from
human exposure or mechanistic knowledge con-
tributed to the assessment. The remaining 93
chemicals were considered unclassifiable as to
their human carcinogenicity (D; 53) or to be pos-
sible human carcinogens (C; 40), based on animal
data considered inadequate to support a stronger
classification (Table 1).
Overall, of those 160 chemicals lacking even
limited human data but possessing animal data,
the EPA considered the animal data inadequate
to support the substantially useful classifications
of probable human carcinogen or probable human
non-carcinogen in the majority of cases (93/160;
58.1%, 95% CI: 50.4–65.5).
Comparison of EPA and IARC human
Of those 177 chemicals that had received a human
carcinogenicity classification from the EPA based
on human or animal data (A, B1, B2, C, D with ani-
mal data, or E), 128 were also assessed by the IARC.
Of these, 17 were considered by the EPA to possess
at least limited human data (A or B1), and the
remaining 111 EPA carcinogenicity classifications
were primarily reliant on animal data.
For those 17 chemicals considered by the EPA to
possess at least limited human data, overall EPA clas-
sifications were not found to differ significantly from
those predicted by IARC classifications (χ2 = 0.291,
df = 1, p = 0.5896; Table 3).N.B. Chi-squared analy-
sis does not allow comparison when one category lacks
any data. Hence acrylonitrile, assessed as the only
possible human carcinogen by the IARC, but as a
probable human carcinogen (B1) by the EPA, was
excluded, yielding a more conservative result.
However, for those 111 chemicals considered by the
EPA to lack even limited human data, but to possess
animal data, EPA and IARC classifications were very
significantly different overall (χ2 = 215.548, df = 2,
p < 0.0001; Figure 1).To permit chi-squared analysis,
methacrylate, assessed as unclassifiable by the IARC,
but as the only probable human non-carcinogen by
the EPA, was excluded, yielding a more conservative
The data reveal that the EPA was much more likely
than the IARC to assign carcinogenicity classifications
indicative of greater human hazard. The numbers of
chemicals classified by the EPA as probable human
carcinogens (60 chemicals) compared to all other cat-
egories (51 chemicals) were very significantly differ-
ent from those predicted by the IARC, for which the
equivalent numbers of chemicals were 12 and 99
(χ2 = 215.273, df = 1, p < 0.0001). Similar disparities
were found for possible human carcinogens
(χ2= 19.771, df = 1, p < 0.0001) and unclassifiable
chemicals (χ2 = 24.378, df = 1, p < 0.0001).
Comparison of the individual classifications of
these 111 chemicals revealed that 67 (60.4%) were
assigned an EPA carcinogenicity classification
indicative of greater human hazard, 38 (34.2%)
were assigned an equivalent classification, and 6
(5.4%) were assigned a classification indicative of
lower human hazard than the corresponding IARC
classification of the same chemical.
Differing EPA and IARC human
Based on EPA figures alone, the predictivity of ani-
mal carcinogenicity data for human hazard, and
Table 2: IARC human carcinogenicity classifications of agents published in the IARC
IARC human carcinogenicity classification Number of chemicals% of total
2A: Probable Human Carcinogen
2B: Possible Human Carcinogen
4: Probable Human Non-Carcinogen
Definite Human Carcinogen88
Data source: IARC Monographs Programme on the Evaluation of Carcinogenic Risks to Humans, Volumes 1–82, 1
22 A. Knight et al.
hence its utility in deriving substantially useful
human carcinogenicity classifications, is clearly
questionable. Of those 160 IRIS chemicals lacking
even limited human data but possessing animal
data, the EPA considered the animal data
inadequate to support the substantially useful clas-
sifications of probable human carcinogen or non-
carcinogen in the majority (93) of cases.
Classifications of definite human carcinogen relied
on the existence of convincing human data.
Classifications of unclassifiable or possible human
carcinogen were not considered substantially useful
for risk assessment or regulatory purposes, and are
excluded from the NTP’s annual Report on
However, IARC assessments of the same chemi-
cals reveal that the human utility of animal car-
cinogenicity data is probably even lower than
indicated by EPA figures. EPA and IARC carcino-
genicity classifications were similar only for those
chemicals having human data. For those lacking
human data, the EPA was much more likely than
the IARC to assign carcinogenicity classifications
indicative of greater human hazard. Of chemicals
lacking human data assessed by both agencies, the
EPA classified 61 chemicals as probable human car-
cinogens or non-carcinogens, primarily on the basis
of their animal data. In contrast, the IARC classi-
fied only 12 chemicals similarly, assessing the
remainder as unclassifiable or as possible human
Given that the IARC is recognised as one of the
most authoritative sources of information on poten-
tial human carcinogens (20, 24), it is implausible
that IARC assessments would generally be inaccu-
rate or based on incomplete data. Consequently, the
significant differences in human carcinogenicity
classifications of identical chemicals between the
IARC and the EPA indicate that:
1. in the absence of significant human data, the
EPA is over-reliant on animal carcinogenicity
2. as a result, the EPA tends to over-predict car-
cinogenic risk; and
3. the true predictivity for human carcinogenicity
of animal data is even poorer than is indicated
by EPA figures alone.
Differences in EPA and IARC human
Both the EPA and the IARC include a wide range of
data in their carcinogenicity assessments. The
Table 3: IARC classifications of EPA chemicals possessing significant human data (EPA
categories A or B1)
Human carcinogenicity classificationEPAIARC
Human Carcinogen (A)
Probable Human Carcinogen (B1)
Possible Human Carcinogen
Data sources: The EPA Integrated Risk Information System database, 1 January 2004, and the IARC Monographs
Programme on the Evaluation of Carcinogenic Risks to Humans, Volumes 1–82, 1 January 2004.
Figure 1: EPA and IARC human
carcinogenicity classifications of
chemicals considered by the EPA
to lack human data but to
possess animal data
= IARC; = EPA; * = p < 0.0001.
Data sources: The EPA Integrated Risk Information
System database, 1 January 2004, and the IARC
Monographs Programme on the Evaluation of
Carcinogenic Risks to Humans, Volumes 1–82, 1
human carcinogenicity classification
No. of chemicals (total 111)
Poor predictivity of carcinogenicity studies 23
major types of evidence considered include human
epidemiological studies and case reports, or, more
rarely, randomised trials; and lifetime exposure
studies in test animal species. Conventional stan-
dardised rodent carcinogenicity studies use at least
50 animals of each sex per dose group in each of
three treatment groups and a concurrent control
group, and last for 18 to 24 months. Assays in
genetically engineered rodents may also be consid-
ered, particularly with a view to elucidating the
chemical or genetic mechanisms of carcinogenesis.
Such rodents may have activated oncogenes intro-
duced (transgenic rodents) or tumour suppressor
genes deleted (knockout rodents). Also considered,
where available, are supporting data from short-
term genotoxicity tests, such as standard bacterial
and mammalian in vitro and in vivo tests, and data
describing preneoplastic lesions, tumour pathology,
toxicological effects other than cancer, metabolic
and toxicokinetic properties, physicochemical
parameters, structure-activity relationships, and
data concerning analogous biological agents. On
occasion, specific additional studies may be com-
missioned to fill important knowledge gaps. Both
agencies aim to include all pertinent data in deriv-
ing a weight-of-evidence assessment of human car-
However, three key differences between the
approaches of the EPA and the IARC may explain
their very significantly different human carcino-
genicity classifications for identical chemicals.
1. Not every EPA assessment is conducted with the
same scope or depth. The level of detail of an
assessment is a matter of management discre-
tion, which, besides considerations of potential
human and environmental risk from a suspected
carcinogen, also seeks to balance pragmatic con-
siderations such as the time, personnel and
resources required for each particular assess-
ment, with those available at the time, as well as
the time and cost of generating any new data
required. Consequently, the agency’s staff often
conduct screening assessments to decide
whether to invest resources in collecting data for
a full assessment. Such screening assessments
may be based almost entirely on structure-activ-
ity relationships and default assumptions, and
more detailed assessments may not occur (25).
IARC assessments, on the other hand, are
invariably conducted in depth. Each IARC Mono-
graph evaluation results from detailed considera-
tion and discussion by 15 or more internationally-
based scientific experts, and the level of evalua-
tion and deliberation is considered by the IARC to
be considerably in excess of the usual peer review
process used by scientific journals (26).
2. While both agencies prefer data from peer-
reviewed sources, the IARC appears to be more
critical about the standard of the data it accepts
for use in its carcinogenicity assessments. Only
occasionally are data accepted from sources
other than the peer-reviewed scientific litera-
ture, such as government agency reports that
have undergone peer review (26–27). This
decreases the likelihood that data from animal
studies of poor quality (for example, those with
inadequate durations, animal numbers or sur-
vival rates) will be included in IARC assess-
3. As leaders of the US federal agency most respon-
sible for protecting Americans from environ-
mental contaminants in the world’s most
litigious nation, the policy-makers of the EPA
understandably err on the side of caution. The
impacts on EPA policy are almost inevitable, as
illustrated by the EPA Guidelines for
Carcinogen Risk Assessment, which state that:
“The primary goal of EPA actions is protection
of human health; accordingly, as an Agency pol-
icy, risk assessment procedures, including
default options that are used in the absence of
scientific data to the contrary, should be health
protective. Use of health protective risk assess-
ment procedures as described in these cancer
guidelines means that estimates, while uncer-
tain, are more likely to overstate than under-
state hazard and/or risk.” (25).
Such policies have affected EPA carcinogenicity
assessments for many years. In response to a
Congressional directive regarding EPA appropria-
tions for the fiscal year 2000, the EPA undertook an
evaluation of data uncertainty and variability
within its IRIS assessments. A representative sam-
ple of 16 IRIS assessments were subjected to in-
depth evaluation by a panel of six independent
experts in the field of human health risk assess-
ment. Among other criticisms, they concluded that,
despite being advertised as a quantitative, science-
based exercise, where uncertainty existed about the
data upon which decisions were based, the classifi-
cations of some chemicals were, in fact, more reflec-
tive of the EPA policy of favouring classifications
indicative of greater human risk (29). As noted by
the experts, such a policy is consistent with the
EPA’s mission to protect public health and the envi-
ronment by means of conservative limits on human
exposure to carcinogens, where doubt remains
about true carcinogenic risk.
With respect to the use of animal test data, the
EPA Guidelines state that: “In the absence of suffi-
ciently scientifically justifiable mode of action infor-
mation, EPA generally takes public health
protective, default positions regarding the interpre-
tation of toxicologic and epidemiologic data: animal
tumor findings are judged to be relevant to
humans…” (25), and, “tumors observed in animals
24 A. Knight et al.
are generally assumed to indicate that an agent
may produce tumors in humans.” (25).
The EPA is strongly defensive of its position:
“The default option is that positive effects in animal
cancer studies indicate that the agent under study
can have carcinogenic potential in humans… This
option is a public health-protective policy, and it is
both appropriate and necessary, given that we do
not test for carcinogenicity in humans…”. Despite
strong indications from numerous investigations (4,
6–8, 30–36), the EPA seems reluctant to acknowl-
edge the extent of error this may incur, and states
that: “The extent to which animal studies may yield
false positive indications for humans is a matter of
scientific debate.” (25).
However, EPA carcinogenicity assessments are
not necessarily inferior to those of other US regula-
tory agencies. In their survey of 350 representative
chemicals, Viscusi and Hakes (37) found that the
human carcinogenicity assessments of other US
regulatory authorities, particularly the Food and
Drug Administration and the Occupational Safety
and Health Administration, are based even less on
an accurate assessment of carcinogenicity data than
are those of the EPA.
Results from IARC Monographs surveys
The poor human predictivity of animal carcino-
genicity studies was also demonstrated in 1993 by
Tomatis and Wilbourn (24), who surveyed the 780
chemical agents or exposure circumstances evalu-
ated and listed within Volumes 1–55 of the IARC
Monograph series (38). Of these, 502 (64.4%) were
classified as having definite or limited evidence of
animal carcinogenicity, and 104 (13.3%) as definite
or probable human carcinogens. Virtually all of the
latter group would, of course, have been members
of the former; however, around 398 animal carcino-
gens were considered not to be definite or probable
The positive predictivity of a test is the propor-
tion of positive test outcomes that are truly positive
for the characteristic being tested for, while the
false positive rate refers to the proportion that are
not. Hence, based on these IARC figures, the posi-
tive predictivity of the animal bioassay for definite
or probable human carcinogens was only around
20.7% (104/502), while the false positive rate was a
disturbing 79.3% (398/502).
More-recent IARC classifications indicate little
improvement in the positive predictivity of the
animal bioassay for human carcinogens. By 1
January 2004, a decade later, only 105 additional
agents had been added to the 1993 figure, yielding
a total of 885 agents or exposure circumstances
listed in the IARC Monographs (39). Not surpris-
ingly, the proportion of definite or probable
human carcinogens resembled the 1993 figure of
13.3%. By 2004, only 9.9% of these 885 were clas-
sified as definite human carcinogens, and only
7.2% as probable human carcinogens, yielding a
total of 17.1% (Table 2).
Results from NTP and other surveys
Surveys by other investigators have also demon-
strated the poor human predictivity of animal car-
cinogenicity data. After examining the studies of
471 substances contained within the NTP carcino-
genicity database as of 1 July 1998, Haseman (30)
concluded that although 250 (53.1%) produced car-
cinogenic effects in at least one sex–species group,
the actual proportion posing a significant carcino-
genic risk to humans was probably far lower, for
reasons such as interspecies differences in mecha-
nisms of carcinogenicity. Similarly, around half of
all chemicals tested on animals and included in the
comprehensive CPDB, whether natural or syn-
thetic, give positive results (7).
Rall (4) estimated that only around 10% of chem-
icals are truly carcinogenic to humans. Ashby and
Purchase (31) speculated that all chemicals would
eventually display some carcinogenic activity, if
tested in sufficient rodent strains. Even common
table salt has been classified as a tumour promoter
in rats (32).
Fung et al. (33) estimated that, if all 75,000 chem-
icals in use were tested for carcinogenicity via the
standard NTP bioassay, significantly less than 50%
would prove carcinogenic in animals, and less than
5–10% would warrant further investigation. They
suggested that the higher positivity rate recorded
was due to chemical selection based on an a priori
suspicion of carcinogenicity. However, examination
of the carcinogenicity literature reveals that chemi-
cals are selected for study for many reasons other
than an a priori suspicion, including production vol-
umes, occupational and environmental exposure
risks, and investigations of carcinogenesic mecha-
nisms (34). Despite this, the positivity rate of the
carcinogenicity bioassay in the general literature
remains around 50% (7).
Carcinogenicity bioassays fail human
Despite the heavy reliance for the last several
decades on rodent carcinogenicity data in the regu-
lation of human exposures, the conventional rodent
bioassay has never been formally validated against
human data. On the contrary, validation studies
have found the rodent bioassay to be lacking in
human specificity (i.e. in the ability to identify
human non-carcinogens), resulting in false positive
outcomes, or even human sensitivity (i.e. the ability
to detect human carcinogens at all), depending on
Poor predictivity of carcinogenicity studies 25
the data interpretation method used. Ennever and
Lave (35) showed that neither of the two com-
monly-used interpretations of rodent carcinogenic-
ity data provide conclusions about human
carcinogenicity that are supported by existing data.
If a risk-avoidance interpretation is used, in which
any positive result in male or female mice or rats is
considered positive, then nine of the 10 known
human carcinogens among the hundreds of chemi-
cals tested by the NTP are positive (36), but so are
an implausible 22% of all chemicals tested (33). If a
less risk-sensitive interpretation is used, whereby
only chemicals positive in both mice and rats are
considered positive, then only three of the six
known human carcinogens tested in both species
are positive (36). The former interpretation could
result in the needless denial of potentially useful
chemicals to society, while the latter could result in
widespread human exposure to undetected human
By 1998, only about 2000 (2.7%) of the 75,000
industrial chemicals in use and listed in the EPA’s
Toxic Substances Control Act inventory, had been
tested for carcinogenicity (40). The cost of testing
these 2.7% of industrial chemicals was millions of
animal lives (9, 41), millions of hours of work by
skilled personnel (41), and hundreds of millions of
dollars (10, 12).
The most important use of the animal data thus
derived is the regulation of human exposure to
potential carcinogens by governmental agencies
such as the EPA. However, we found that the
human predictivity of animal carcinogenicity data
was inadequate for the EPA to derive substantially
useful human carcinogenicity classifications for the
majority (58.1%) of chemicals studied.
Even when the EPA was able to derive substan-
tially useful human carcinogenicity classifications,
primarily on the basis of animal carcinogenicity
data, there was a profound discordance with assess-
ments of identical chemicals by the IARC, a leading
international authority on carcinogenicity assess-
ments, seriously undermining the reliability of EPA
classifications. For those classifications primarily
reliant on animal data, the EPA was much more
likely than the IARC (p < 0.0001) to assign classifi-
cations indicative of greater human risk, indicating
that: 1) in the absence of significant human data,
the EPA is over-reliant on animal carcinogenicity
data for extrapolating to human hazard; 2) as a
result, the EPA tends to over-predict carcinogenic
risk to humans; and 3) the true predictivity for
human carcinogenicity of animal data is even
poorer than indicated by EPA figures alone.
EPA human carcinogenicity classifications
appear less scientifically-based than those of the
IARC, due to: 1) varying depths of EPA assess-
ments, as a result of resource constraints; 2) less
rigorous standards required of data incorporated
into EPA assessments; and 3) an EPA public
health-protective policy that seeks to err on the side
of caution by assuming that tumours in animals are
indicative of human carcinogenicity.
The sensitivity of the conventional rodent bioas-
say in detecting human carcinogens for some
sex–species groups is not in question. However, its
poor human predictivity severely limits its utility
for assessing human hazard.
This research was partly funded by the Physicians
Committee for Responsible Medicine, Washington
Received 6.8.05; received in final form 18.12.05; accepted
for publication 19.12.05.
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