Pharmacokinetic data reduce uncertainty in the acceptable daily intake for benzoic acid and its salts.

The current acceptable daily intake (ADI) for benzoic acid and its salts as food additives is 0-5 mg/kg body weight. This accounts for a total uncertainty factor (UF) of 100, which includes a default factor of 10 for interspecies differences. Based on pharmacokinetic data in rodents and humans, we derived a chemical-specific adjustment factor (CSAF) of 2 for the pharmacokinetic component of the interspecies UF. Additional analyses indicate that this CSAF is conservative and interspecies differences between rats and humans are likely closer to unity. Human clinical studies indicate that the pharmacokinetics of benzoic acid and its salts are similar in children and adults, and that there is a lack of adverse events in humans at doses comparable to the no observed adverse effect level (NOAEL) in rodents; this suggests that the pharmacokinetic UF for intraspecies variability, as well as the pharmacodynamic components of the UFs, may also be reduced, although we did not calculate to what degree. In conclusion, the total UF can be reduced to 50 (2 for interspecies differences in pharmacokinetics, 2.5 for interspecies differences in pharmacodynamics, and 10 for intraspecies variability), which would increase the ADI to 0-10 mg/kg body weight.

Pharmacokinetic modeling of carisoprodol and meprobamate disposition in adults.

Carisoprodol is a widely prescribed muscle relaxant and is also a drug known to be a subject to abuse. Despite the fact that carisoprodol has been available for prescription since 1959, a number of gaps in our knowledge of the toxicokinetics of this common drug exist. For example, the volume of distribution (Vd) for carisoprodol in humans has not been reported. A two-compartment pharmacokinetic model describing carisoprodol metabolism and that of the primary metabolite, meprobamate, was developed to better understand the pharmacokinetics of this drug. The model accounts for first pass metabolism of carisoprodol and was able to replicate the data from several previously reported data sets. Based on an analysis of four different data sets, the Vd for carisoprodol ranged from 0.93 to 1.3 L/kg, while that for meprobamate ranged from 1.4 to 1.6 L/kg. The model was also used to estimate the probable dose of this drug in an individual where questions concerning the drug's role in her death had been posed. The model may, therefore, have significant utility for estimating doses of carisoprodol in medicolegal cases.

Historical perspective on the use of animal bioassays to predict carcinogenicity: evolution in design and recognition of utility.

The animal testing protocols used today to evaluate the carcinogenicity of chemicals are very different from those used in the earlier part of the 20th century. To explore how cancer bioassays have changed over time, we surveyed the literature discussing test design and interpretation from the 1930s to the present. We also analyzed compendia of bioassays published by the US Public Health Service (US PHS) from 1938 to 1978, and evaluated the data to understand the evolution of testing methodology (e.g., animals used, test duration) and the types of chemicals being studied. The cancer bioassay evolved in several stages. At the beginning of the 20th century, animal bioassays were primarily used to re-create known human diseases, whereas in the 1940s to 1960s, animal bioassays were largely used to evaluate the safety of chemicals in foods, drugs, and cosmetics. Beginning in the late 1960s and 1970s, chemicals primarily associated with occupational or environmental exposures were also evaluated. Testing strategies now emphasize a suite of tests including multiple in vitro tests and both short-term and long-term animal tests. The objectives of testing are broader, too, with test goals encompassing information regarding mode of action and other parameters aimed at evaluating potential species differences (e.g., in toxicokinetics) and their relevance for evaluating human risks. It is important to consider this evolution when evaluating the testing methodology and scientific conclusions in earlier eras. As toxicology continues to develop, testing methods will continue to change in concert with increased knowledge and understanding.

An evaluation of surrogate chemical exposure measures and autism prevalence in Texas.

There is currently considerable discussion in the scientific community as well as within the general public concerning the role mercury (Hg) exposures may play in the apparent increased incidence of neurodevelopmental disorders (particularly autism) in children. Although the primary focus of this debate has focused on ethylmercury from vaccinations, linkage to other sources of Hg has been proposed. An ecologic association between 2001 Toxic Release Inventory (TRI; www.epa.gov/tri) data for Hg and 2000-2001 school district autism prevalence was previously reported in Texas. Evaluations using industrial release data as surrogate exposure measures may be problematic, particularly for chemicals like Hg that have complex environmental fates. To explore the robustness of TRI-based analyses of the Hg-autism hypothesis in Texas, a detailed analysis was undertaken examining the extent of the ecological relationship during multiple years and examining whether surrogate exposure measures would yield similar conclusions. Using multilevel Poisson regression analysis and data obtained from a number of publicly available databases, it was found that air Hg release data were significantly associated with autism prevalence in Texas school districts when considering data for 2001 and 2002 (2001: RR = 4.45, 95% CI = 1.60-12.36, 2002: RR = 2.70, 95% CI = 1.17-6.15). Significant associations were not found using data from 2003 to 2005. A significant association was not observed when considering air Hg data for 2000 or 2001 and school district autism prevalence data for 2005-2006 or 2006-2007, an analysis allowing for a 5-yr time period between presumed exposure and entry into the public school system (2000: RR = 1.03, 95% CI = 0.59-1.83, 2001: RR = 0.94, 95% CI = 0.59-1.47). Significant associations were not observed for any year nor for the time lagged analyses when censored autism counts were replaced by threes instead of zeros. An evaluation of TRI air emissions data for several other pollutants did not find significant associations except for nickel (RR = 1.71, 1.12-2.60), which has no history of being associated with neurodevelopmental disorders. An evaluation using downwind location from coal-fired power plants as the exposure surrogate variable also did not yield statistically significant results. The analysis suggests Hg emissions are not consistently associated with autism prevalence in Texas school districts. The lack of consistency across time may be the result of the influence of a more significant factor which remains unidentified. Alternatively, it may be that the significant association observed in 2001 and 2002 does not represent a true causal association.

A proposed methodology for selecting a trichloroethylene inhalation unit risk value for use in risk assessment.

U.S. EPA's 2001 draft assessment of trichloroethylene (TCE) toxicity reviews the existing human and animal data on TCE carcinogenicity and proposes a 20-fold range of cancer potency values for use in risk assessment. Each value in the range is derived from a different source of data, either animal bioassays or epidemiology studies, and thus the range does not represent a distribution which can be characterized by statistical parameters such as a mean or 95% confidence interval. The U.S. EPA suggests users choose a single slope factor from among those it describes as appropriate for the population of interest and mode of exposure, but little guidance is given for making this choice. We propose an approach for determining the most scientifically defensible carcinogenic inhalation unit risk estimate from the range of slope factors developed by U.S. EPA, one that relies on accepted principles for evaluating scientific studies. Based on these considerations, we identify the most appropriate interim unit risk for low-level inhalation exposure as 9 x 10(-7) per microg/m(3). This approach may have fairly broad utility if U.S. EPA elects to use a similar approach in future assessments of other chemicals.

Risk evaluation of occupational exposure to methylene dianiline and toluene diamine in polyurethane foam.

Methylene diphenylisocyanate (MDI) and toluene diisocyanate (TDI) are widely used in industry to produce polyurethane foam products. Small amounts of methylenedianiline (MDA) and toluene diamine (TDA) are released during MDI and TDI polymerization and may be present in newly finished polyurethane foam parts. MDA and TDA concentrations in foam decline exponentially within several hours of demolding. MDA and the 2,4-isomer of TDA are known animal carcinogens and, in addition, have significant non-carcinogenic health effects. Our goal was to determine whether worker exposure to MDA or TDA in freshly produced polyurethane foams was associated with unacceptable health risks. Sampling and analysis of the fresh foam indicated that MDA and TDA concentrations varied considerably among products, but concentrations in all materials evaluated declined rapidly over time. We found that, under a worst-case exposure scenario, cancer risks from TDA exposure were approximately 5 x 10(-6), whereas cancer risks from MDA exposure resulted in a tumorigenic margin of exposure (MOE) of 85 000. Non-cancer chronic hazard indices were well below 1.0. Therefore, the potential cancer and non-cancer health risks from MDA or TDA exposure to newly manufactured foam parts appear to fall well within acceptable health risk criteria.

Interspecies differences in susceptibility to perturbation of thyroid homeostasis: a case study with perchlorate.

Despite many physiological similarities, humans and rats exhibit notably different susceptibilities to thyroid perturbation. Considerable research has recently been conducted on the thyroid-active chemical perchlorate, a chemical of emerging environmental and regulatory interest. While the data indicate humans and rats exhibit similar dose-response relationships in terms of acute inhibition of thyroidal iodide uptake, the two species appear to exhibit notable differences in terms of thyroid hormone response, the toxicologically significant consequence of iodide uptake inhibition. We analyzed dose-response data for changes in serum T(3), T(4), and TSH levels from studies in humans, rats, mice, and rabbits. We found that thyroid homeostasis in the rat appears to be strikingly more sensitive to perchlorate than any of the other species. Rats exhibited an increase in serum TSH at 0.1mg/kg-day whereas other species remained unresponsive even at doses of 10mg/kg-day. Less pronounced but consistent effects were seen with serum T(3) and T(4). These cross-species comparisons provide strong evidence that data obtained from rat studies should be critically evaluated for their relevance to humans. If rat data are used to develop toxicity criteria for perchlorate, we propose that this is an instance where an inter-species uncertainty factor less than one is supportable. DISCLOSURE STATEMENT: One of the authors (BDB) has been hired by Lockheed Martin Corporation as an expert in litigation involving perchlorate. A portion of the initial research presented in this paper was conducted in conjunction with her role in that matter.

Effect of methylmercury on midbrain cell proliferation during organogenesis: potential cross-species differences and implications for risk assessment.

5'-bromodeoxyuridine (BrdU) labeling was employed to explore the effects of methylmercury (MeHg) on cell cycle kinetics in the developing rat midbrain during gestational days (GDs) 11 to 14. Contrary to what has been previously reported in mice, no effects of MeHg on cell cycle kinetics were observed up to embryonic brain concentrations of 3-4 microg/g. The absence of an effect was confirmed using stereology and counts of midbrain cell number. Treatment with colchicine, the positive control, resulted in significant effects on cell cycle kinetics in the developing rat midbrain. The parallelogram method, borrowed from genetic toxicology, was subsequently used to place the data obtained in the present study in the context of previously collected in vitroand in vivo data on MeHg developmental neurotoxicity. This required developing a common dose metric (microg Hg/g cellular material) to allow in vitro and in vivo study comparisons. Evaluation suggested that MeHg's effects on neuronal cell proliferation show a reasonable degree of concordance across mice, rats, and humans, spanning approximately an order of magnitude. Comparisons among the in vivo data suggest that humans are at least or more sensitive than the rodent and that mice may be a slightly better model for MeHg human developmental neurotoxicity than the rat. Such comparisons can provide both a quantitative and a qualitative framework for utilizing both in vivo and in vitro data in human health risk assessment.

Methylmercury distribution in the pregnant rat and embryo during early midbrain organogenesis.

BACKGROUND: The period of neurogenesis represents a window of susceptibility for in utero methylmercury (MeHg) exposure. This study examined the toxicokinetics of potentially neurotoxic doses of MeHg during neurogenesis in the developing rat to provide additional information in the areas of mercury speciation and inter-study variability. METHODS: Pregnant Sprague-Dawley rats were dosed s.c. with 5-22 mg/kg MeHg on Day 11 of gestation to target rapidly dividing cells of the developing midbrain. Maternal liver, kidney, skin, blood, placenta, and the embryonic body and brain were evaluated for total and inorganic mercury content at 24, 48, and 72 hr after dosing. Tissue Hg partitioning ratios derived from our data were then compared to those derived from previous studies. RESULTS: Mercury was present in all tissues examined by 24 hr after dosing, and levels remained relatively stable over the subsequent 2 days in most tissues. The exceptions were the maternal blood and kidney, in which total mercury decreased significantly over the three days after dosing. Inorganic mercury concentrations were similarly stable over time. At maternal MeHg doses above 12 mg/kg, non-linearities were observed in mercury accumulation in the embryo, placenta and maternal liver. The mercury tissue partitioning coefficients ranged from 0.09 for maternal blood:embryo to 1.97 for maternal blood:kidney. CONCLUSIONS: Our observations at the 5 mg/kg dose were consistent with those of previous studies that involved evaluations at slightly later gestational times. The estimates of tissue partitioning coefficients we derived using multiple studies provide valuable insight into the effects of inter-study variability.

A computational model for neocortical neuronogenesis predicts ethanol-induced neocortical neuron number deficits.

We have developed a computational model that allows for the evaluation of normal and perturbed neurodevelopmental processes. This mathematical construct is used to test the hypothesis that reduced neuronal production is the critical mechanism behind fetal alcohol syndrome. Model predictions of normal neurodevelopment match independent stereological measures but challenge estimates generated using a previously published model of normal neocortical neuronogenesis. Evaluation of data showing an increased cell cycle length after prenatal exposure to ethanol during neocortical neuronogenesis yields predictions of cellular deficits that can account for the permanent neocortical neuronal loss seen in rodents exposed to ethanol concentrations of public health relevance.

A comparison of 1H8- and 2H8-toluene toxicokinetics in men.

1. To examine the bioequivalence of an isotope-labelled tracer to study toxicant disposition, we conducted 33 controlled human exposures to a mixture of 50 ppm 1H8-toluene and 50 ppm 2H8-toluene for 2 h, and measured concentrations in blood and breath, and metabolite levels in urine for 100 h post-exposure. 2. A physiologically based kinetic (PBK) model found that compared with 1H8-toluene, 2H8-toluene had a 6.4+/-13% (mean+/-SD) lower AUC, a 6.5+/-13% higher systemic clearance (1.46+/-0.27 versus 1.38+/-0.25 l/h-kg), a 17+/-22% larger terminal volume of distribution (66.4+/-14 versus 57.2+/-10 l/kg) and a 9.7+/-26% longer terminal half-life (38+/-12 versus 34+/-10 h) (p < 0.05 for all comparisons). 3. The higher 2H8-toluene clearance may have been due to an increased rate of ring oxidation, consistent with the 17% higher observed fraction of 2H5- versus 1H5-cresol metabolites in urine. 4. The larger terminal volume and half-lives for 2H8-toluene suggested a higher adipose tissue/blood partition coefficient. 5. Observed isotope differences were small compared with interindividual differences in 1H8-toluene kinetics from previous studies. 6. The PBK model allowed us to ascribe observed isotope differences in solvent toxicokinetics to underlying physiologic mechanisms.

Comparison of IEUBK model predictions and actual blood lead values at a former battery recycling site.

This paper presents an evaluation of US EPA's integrated exposureuptake biokinetic model for lead (IEUBK model) using data obtained during emergency removal operations at a former lead-acid battery recycling plant and the surrounding community. Data employed in the study include soil lead and interior dust lead, air lead levels collected at the site perimeter, drinking water lead levels at the community water main and blood lead data collected from an annual blood lead monitoring programme conducted over a four year period during the remediation activities.Geometric mean soil and dust concentrations were found to be a better predictor of blood lead than arithmetic mean data. However, weight based dust lead data were believed to be an inappropriate measure of dust lead levels. Estimates of household dust lead concentrations based upon surface loading data (µg m(-2)) yielded blood lead predictions which were more consistent with data collected in the blood lead monitoring programme.