[Show abstract][Hide abstract] ABSTRACT: 1,4-Dioxane is found in consumer products and is used as a solvent in manufacturing. Studies in rodents show liver tumors to be consistently reported after chronic oral exposure. However, there were differences in the reporting of non-neoplastic lesions in the livers of rats and mice. In order to clarify these differences, a reread of mouse liver slides from the 1978 NCI bioassay on 1,4-dioxane in drinking water was conducted. This reread clearly identified dose-related non-neoplastic changes in the liver; specifically, a dose-related increase in the hypertrophic response of hepatocytes, followed by necrosis, inflammation and hyperplastic hepatocellular foci. 1,4-Dioxane does not cause point mutations, DNA repair, or initiation. However, it appears to promote tumors and stimulate DNA synthesis. Using EPA Guidelines (2005), the weight of the evidence suggests that 1,4-dioxane causes liver tumors in rats and mice through cytotoxicity followed by regenerative hyperplasia. Specific key events in this mode of action are identified. A Reference Dose (RfD) of 0.05 mg/kg-day is proposed to protect against regenerative liver hyperplasia based on a benchmark dose (BMD) approach. Based on this RfD, a Maximum Contaminant Level Goal of 350 μg/L is proposed using a default relative source contribution for water of 20%.
Regulatory Toxicology and Pharmacology 01/2014; · 2.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A biomathematical model was previously developed to describe the long-term clearance and retention of particles in the lungs of coal miners. The model structure was evaluated and parameters were estimated in two data sets, one from the United States and one from the United Kingdom. The three-compartment model structure consists of deposition of inhaled particles in the alveolar region, competing processes of either clearance from the alveolar region or translocation to the lung interstitial region, and very slow, irreversible sequestration of interstitialized material in the lung-associated lymph nodes. Point estimates of model parameter values were estimated separately for the two data sets. In the current effort, Bayesian population analysis using Markov chain Monte Carlo simulation was used to recalibrate the model while improving assessments of parameter variability and uncertainty. When model parameters were calibrated simultaneously to the two data sets, agreement between the derived parameters for the two groups was very good, and the central tendency values were similar to those derived from the deterministic approach. These findings are relevant to the proposed update of the ICRP human respiratory tract model with revisions to the alveolar-interstitial region based on this long-term particle clearance and retention model.
Regulatory Toxicology and Pharmacology 02/2013; · 2.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The available toxicity information for boron was reevaluated and four appropriate toxicity studies were selected in order to derive a tolerable daily intake (TDI) using newly proposed uncertainty factors (UFs) presented in Hasegawa et al. (2010). No observed adverse effect levels (NOAELs) of 17.5 and 8.8 mg B/kg/day for the critical effect of testicular toxicity were found in 2-year rat and dog feeding studies. Also, the 95% lower confidence limit of the benchmark doses for 5% reduction of fetal body weight (BMDL(05)) was calculated as 44.9 and 10.3 mg B/kg/day in mouse and rat developmental toxicity studies, respectively. Measured values available for differences in boron clearance between rats and humans and variability in the glomerular filtration rate (GFR) in pregnant women were used to derive chemical specific UFs. For the remaining uncertainty, newly proposed default UFs, which were derived from the latest applicable information with a probabilistic approach, and their subdivided factors for toxicokinetic and toxicodynamic variability were applied. Finally, overall UFs were calculated as 68 for rat testicular toxicity, 40 for dog testicular toxicity, 250 for mouse developmental toxicity and 78 for rat developmental toxicity. It is concluded that 0.13 mg B/kg/day is the most appropriate TDI for boron, based on rat developmental toxicity.
Regulatory Toxicology and Pharmacology 11/2012; · 2.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We propose new uncertainty factors (UFs) and a new subdivision of default factors in chemical risk assessment using a probabilistic approach based on the latest applicable information. Rounded values of 150 for mice, 100 for hamsters and rats, and 40 for rabbits, monkeys and dogs for inter- and intra-species differences (UF(AH)) were derived from the probabilistic combination of two log-normal distributions. Further calculation of additional UFs when chronic data (UF(S)) or NOAEL (UF(L)) are lacking was conducted using available log-normal distribution information. The alternative UF(S) and UF(L) values of 4 are considered to be appropriate for both cases where data are lacking. The default contributions of inter-species difference (UF(A)) and intra-species difference (UF(H)) to the UF(AH) of 100 for hamsters and rats as an example are considered to be 25 and 4, respectively. The UF(A) of 25 was subdivided into 25(0.6) (i.e., 7.0) for pharmacokinetics (PK) (UF(A,PK)) and 25(0.4) (i.e., 3.6) for pharmacodynamics (PD) (UF(A,PD)), and the UF(H) of 4 was evenly subdivided into 4(0.5) (i.e., 2) (UF(H,PK) and UF(H,PD)), to account for chemical-specific difference data between humans and laboratory animals for PK and/or PD. These default UFs, which come from actual experimental data, may be more appropriate than previous default UFs to derive tolerable daily intake values.
Regulatory Toxicology and Pharmacology 11/2010; 58(2):237-42. · 2.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The current emphasis on occupational exposures to diacetyl has led to new research on its effects. We evaluated whether the data are sufficient to support a transition from a hazard-based risk management approach to a quantitative occupational risk assessment approach, characterized by developing a health-based occupational exposure limit (OEL). Inhalation health effects data were evaluated and issues and uncertainties related to occupational risk assessment needs were identified. A systematic hazard characterization, supported by both the toxicology and epidemiology literature, showed that the respiratory tract effects of diacetyl are the primary end points of relevance for developing an OEL. In an effort to provide a systematic approach for the analysis of the issues that need to be considered in developing an occupational risk assessment for diacetyl, a potential OEL was derived. A concentration-response assessment was completed using tracheobronchial effects in mice as the critical effect. The resulting benchmark concentration (lower bound estimate or BMCL) was adjusted to a human equivalent concentration of 1.8 ppm. A composite uncertainty factor of 10 was recommended to account for extrapolation from an adjusted BMCL from an animal study and for human variability in sensitivity and taking into account other uncertainties in the overall database. The resulting OEL recommendation of 0.2 ppm as a time-weighted average (TWA) was supported by the current occupational epidemiology literature. This evaluation showed that a health-based OEL value can be derived for diacetyl with moderate to high confidence.
Regulatory Toxicology and Pharmacology 11/2010; 58(2):285-96. · 2.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: An independent peer expert panel was convened under the auspices of the Alliance for Risk Assessment (ARA) to review toxicology data and derive oral Reference Doses (RfDs) for four environmental degradates of the acetanilide herbicides, alachlor and acetochlor. The degradates included in this evaluation were (1) alachlor tertiary-ethanesulfonic acid (ESA), (2) alachlor tertiary-oxanilic acid (OXA), (3) acetochlor ESA, and (4) acetochlor OXA. Each degradate was judged to have sufficient data for developing low to medium confidence RfD, with use of an additional uncertainty factor (UF) to cover data gaps. Body weight decreases were identified as the most sensitive treatment-related adverse effect for RfD development. A composite UF of 1000 (10 for human variability in sensitivity, 10 for interspecies differences in sensitivity, and 10 for subchronic to chronic and database deficiency combined; i.e., 10(A)x10(H)x10(S&D)) for each degradate was considered reasonable, while noting that an argument could be made for an UF of 3000 (10(A)x10(H)x30(S&D)). Based on the available data, an oral RfD of 0.2 mg/kg-day is recommended for both acetochlor ESA and acetochlor OXA and an oral RfD of 0.8 mg/kg-day is recommended for both alachlor ESA and alachlor OXA.
Regulatory Toxicology and Pharmacology 03/2010; 57(2-3):220-34. · 2.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Acrylamide is commonly found in various foods. Cancer studies in rats have reported increases in tumors of the thyroid, mammary tissues, tunica vaginalis of the testis, and sometimes tumors at other sites. We review relevant studies on acrylamide’s DNA toxicity, tumor formation and the manner of its tumor formation. We find, as do others, that glycidamide (a metabolite of acrylamide) causes point mutations, but acrylamide does not. We also find that thyroid tumors are most consistently sensitive in rats, being evoked in each of four long-term experiments. We evaluate the common manners of this tumor formation in the thyroid, including both mutagenicity and thyroid growth-stimulation. Consistent with the overall weight of the evidence, we conclude that both of these manners or modes of action may be occurring. We conservatively assume that the mutagenic mode of action determines the low-dose–response and we conclude that growth stimulation likely dominates the response at higher doses. Following US EPA guidelines, we determined that the probit model best reflects the overall data set; this model is also preferred because it better reflects the underlying “decoupled” biology of contributions from potentially two modes of action. We use the probit model to identify a health-protective, linear cancer slope factor (SF) of 0.030 (mg/kg-day)−1 for the low area of the dose–response curve associated with possible mutagenicity. We also identify a Reference Dose (RfD) in the range of 0.05–0.02 mg/kg-day for the high area of the dose–response curve associated with the growth stimulation. This latter value can be used to determine the upper range of risk. This dose–response assessment is briefly summarized in light of other related work.
Regulatory Toxicology and Pharmacology 12/2008; · 2.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We comprehensively re-analyzed the toxicity data for 18 industrial chemicals from repeated oral exposures in newborn and young rats, which were previously published. Two new toxicity endpoints specific to this comparative analysis were identified, the first, the presumed no observed adverse effect level (pNOAEL) was estimated based on results of both main and dose-finding studies, and the second, the presumed unequivocally toxic level (pUETL) was defined as a clear toxic dose giving similar severity in both newborn and young rats. Based on the analyses of both pNOAEL and pUETL ratios between the different ages, newborn rats demonstrated greater susceptibility (at most 8-fold) to nearly two thirds of these 18 chemicals (mostly phenolic substances), and less or nearly equal sensitivity to the other chemicals. Exceptionally one chemical only showed toxicity in newborn rats. In addition, Benchmark Dose Lower Bound (BMDL) estimates were calculated as an alternative endpoint. Most BMDLs were comparable to their corresponding pNOAELs and the overall correlation coefficient was 0.904. We discussed how our results can be incorporated into chemical risk assessment approaches to protect pediatric health from direct oral exposure to chemicals.
Regulatory Toxicology and Pharmacology 05/2007; 47(3):296-307. · 2.13 Impact Factor