Human exposure assessment and the National Toxicology Program.

The National Institute of Environmental Health Sciences/National Toxicology Program (NIEHS/NTP) is developing a new interagency initiative in exposure assessment. This initiative involves the NIEHS, the Centers for Disease Control and Prevention through its National Center for Environmental Health, the National Institute for Occupational Safety and Health, the EPA, and other participating institutes and agencies of the NTP. This initiative will benefit public health and priority setting in a number of ways. First, as discussed above, it will strengthen the scientific foundation for risk assessments by the development of more credible exposure/response relationships in people by improving cross-species extrapolation, the development of biologically based dose-response models, and the identification of sensitive subpopulations and for "margin of exposure" based estimates of risk. Second, it will provide the kind of information necessary for deciding which chemicals should be studied with the limited resources available for toxicological testing. For example, there are 85,000 chemicals in commerce today, and the NTP can only provide toxicological evaluations on 10-20 per year. Third, we would use the information obtained from the exposure initiative to focus our research on mixtures that are actually present in people's bodies. Fourth, we would obtain information on the kinds and amount of chemicals in children and other potentially sensitive subpopulations. Determinations of whether additional safety factors need to be applied to children must rest, in part, upon comparative exposure analyses between children and adults. Fifth, this initiative, taken together with the environmental genome initiative, will provide the science base essential for meaningful studies on gene/environment interactions, particularly for strengthening the evaluation of epidemiology studies. Sixth, efficacy of public health policies aimed at reducing human exposure to chemical agents could be evaluated in a more meaningful way if body burden data were available over time, including remediation around Superfund sites and efforts to achieve environmental justice. The exposure assessment initiative is needed to address public health needs. It is feasible because of recent advances in analytical technology and molecular biology, and it is an example of how different agencies can work together to better fulfill their respective missions.

Implementation of EPA Revised Cancer Assessment Guidelines: Incorporation of Mechanistic and Pharmacokinetic Data.

A workshop entitled "Implementation of EPA Revised Cancer Assessment Guidelines: Incorporation of Mechanistic and Pharmacokinetic Data" was held in Anaheim, California, in 1996 at the 35th Annual Meeting of the Society of Toxicology (SOT). This workshop was jointly sponsored by the Carcinogenesis, Risk Assessment, and Veterinary Specialty Sections of the SOT. The thrust of the workshop was to discuss the scientific basis for the revisions to the EPA Guidelines for cancer assessment and EPA's plans for their implementation. This is the first revision to the original EPA guidelines which have been in use by EPA since 1986. The principal revisions are intended to provide a framework for an increased ability to incorporate biological data into the risk assessment process. Two cases were presented, for chloroform and triclioroethylene, that demonstrated the use of the revised guidelines for specific cancer risk assessments. Using these new guidelines, nonlinear margin of exposure analyses were proposed for these chemicals instead of the linearized multistage model previously used by the EPA as the default method. The workshop participants generally applauded the planned revisions to the EPA guidelines. For the most part, they considered that the revised guidelines represented a positive step which should allow for and encourage the use of biological information in the conduct of cancer risk assessments. Several participants cautioned however that the major problem with cancer risk assessments would continue to be the inadequacy of available data on which to conduct more scientific risk assessments.

Research needs for the risk assessment of health and environmental effects of endocrine disruptors: a report of the U.S. EPA-sponsored workshop.

The hypothesis has been put forward that humans and wildlife species adverse suffered adverse health effects after exposure to endocrine-disrupting chemicals. Reported adverse effects include declines in populations, increases in cancers, and reduced reproductive function. The U.S. Environmental Protection Agency sponsored a workshop in April 1995 to bring together interested parties in an effort to identify research gaps related to this hypothesis and to establish priorities for future research activities. Approximately 90 invited participants were organized into work groups developed around the principal reported health effects-carcinogenesis, reproductive toxicity, neurotoxicity, and immunotoxicity-as well as along the risk assessment paradigm-hazard identification, dose-response assessment, exposure assessment, and risk characterization. Attention focused on both ecological and human health effects. In general, group felt that the hypothesis warranted a concerted research effort to evaluate its validity and that research should focus primarily on effects on development of reproductive capability, on improved exposure assessment, and on the effects of mixtures. This report summarizes the discussions of the work groups and details the recommendations for additional research.

Workshop overview. National Toxicology Program Studies: principles of dose selection and applications to mechanistic based risk assessment.

A workshop entitled "NTP Studies: Principles of Dose Selection and Applications to Mechanistic Based Risk Assessment" was held at the 34th Annual Meeting of the Society of Toxicology in Baltimore, Maryland. The purpose of the workshop was to provide an overview of factors currently considered important in the selection of doses for NTP studies, to describe some of the confounding factors that can result from the indiscriminate use of bioassay data in quantitative risk assessment, and to suggest ways in which information from mechanistic studies or studies of biomarkers of exposure or effect might be used to better advantage in risk assessment.

The importance of biological realism in dioxin risk assessment models.

Mechanistic mathematical models of hepatocarcinogenesis in the female rat were constructed to investigate possible relationships among the Ah, estrogen, and EGF receptors in TCDD hepatocarcinogenicity. Each model generates dose-response curves for the expression of biomarker liver proteins CYP1A1, CYP1A2, and residual plasma membrane EGF receptor consequent to exposure to TCDD. The shapes of the response curves were strongly dependent on the assumed mechanisms of constitutive expression of these proteins. Assuming a constant level of the hepatic Ah receptor, a sigmoidal dose-response of hepatic CYP1A1 to total liver TCDD was computed. However, inclusion of induction of the Ah receptor by TCDD in a physiologically realistic dosimetric model produced a linear low-dose response of CYP1A1. This behavior was computed to arise from the net effect of sublinear response of CYP1A1 mRNA to the concentration of the Ah-TCDD complex and supralinear response of the protein concentration to the mRNA level, illustrating the importance of biological realism in dose-response modeling. The dosimetric model also computed effects of TCDD on the hepatic estradiol concentration and consequent effects on the binding capacity of the EGF receptor and suggests plausible mechanisms for tumor promotion by TCDD. Setting circulating estradiol levels in the model to values typical of the male rat indicated possible sources of the differences in the responses of the EGF receptor and in development of tumors in the two sexes.

Ligand/receptor binding for 2,3,7,8-TCDD: implications for risk assessment.

There is renewed controversy regarding safe exposure levels for dioxin. At the heart of this controversy is the hypothesis that toxic effects of dioxin are receptor-mediated and therefore a "threshold" should exist below which no toxic effects can occur. Our research focuses on the ability of dioxin to alter protein levels in rodent livers. Established effects of exposure to dioxin are the induction of cytochrome P450-1A1 and P450-1A2 and a reduction in the maximal binding of the epidermal growth factor receptor in rat livers. An initiation-promotion protocol was used to study the effects of dioxin in female Sprague-Dawley rats. Animals were administered a single initiating dose of diethylnitrosamine followed by 16 biweekly gavage doses of 2,3,7,8-TCDD. Steady-state pharmacodynamic models were fit to these data assuming a combination of Hill kinetics and Michaelis-Menten kinetics. Two classes of models were developed which postulate two different mechanisms for the constitutive expression and TCDD-induced alterations in the levels of these proteins. The results are consistent with models which follow proportionate response in the low-dose region (no threshold) and with models which allow for a low-dose threshold. In all cases studied, the best fitting model exhibited no "threshold" for the effects of TCDD on the modulation of these proteins. The finding is consistent with the knowledge that for some receptor-mediated responses, there is a proportional relationship between receptor occupancy and biological response, even at low ligand concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Perspectives on risk assessment impact of recent reports on benzene.

Very sensitive methods that can detect the benzene metabolite muconic acid (MA) in the urine of virtually all members of the general population have recently become available and have been used in a few occupational studies as a marker of benzene exposure. Preliminary findings from these studies suggest that urinary MA may be a reliable marker of occupational exposure to greater than 5 ppm benzene. It was also consistently observed that a certain proportion of the general population have urinary MA levels compatible with those seen in persons occupationally exposed to greater than 1 ppm benzene. It is unlikely that these elevated levels can be explained solely as being artifactual. The frequency with which they occur for a given individual, and the duration with which they are maintained, are not known. Information on these two factors is needed in order to adequately assess whether or not these levels present a significant risk for a segment of the general population.

Benzene dosimetry in experimental animals: relevance for risk assessment.

The findings of the studies summarized in this report provide some understanding of the possible role of dosimetry in the different response of the rats and mice to benzene in the long-term bioassay studies. The more sensitive species, the mice, definitely has a higher capacity to metabolize benzene and to metabolize it to more of the putative toxic metabolites than do rats. A major finding of these studies is that in three different animal species, from mice to monkeys, the metabolic pathways leading to production of the putative toxic metabolites appear to be low-capacity, high-affinity pathways that are saturated at relatively low-exposure concentrations. This does not prove, but suggests, that the same may be true in humans. If the total formation of the putative toxic metabolites is predictive of the toxicity of benzene, then the animal studies suggest that calculations of the risk associated with low dose exposures based on the results of animal studies conducted at high doses would underestimate the toxicity of benzene. The current report concerns only dosimetry. Another problem in assessing the risk to humans from benzene exposure is the fact that the animal models do not respond to benzene in the same way as humans. The major concern for humans exposed to benzene, based on epidemiology studies, is the risk of developing acute myelogenous leukemia (Rinksy, 1987). The cancers developed by the rodents on the long-term bioassay studies were at other sites (liver, lung, Zymbal's gland, lymph tissue, ovaries, and mammary gland). There is as yet no good animal model for benzene-induced leukemia. However, it has been suggested that benzene may also increase the incidence of Hodgkin's disease, malignant lymphoma, multiple myeloma and lung cancer in humans, although a statistical basis for this is lacking (Askoy, 1985). It is not unreasonable to assume that whatever form of cancer is induced, the induction is most likely through the reactive metabolites produced from benzene. Therefore, the dosimetry of these metabolites is pertinent. Our studies indicate that benzene metabolite dosimetry data obtained in animals provides data relevant to the estimation of human risks.

Placental markers of human exposure to polychlorinated dibenzofurans and polychlorinated biphenyls: implications for risk assessment.

In 1979, rice oil accidentally contaminated with a mixture of polychlorinated dibenzofurans (PCDFs) and polychlorinated biphenyls (PCBs) was ingested by a large number of individuals in Taiwan. Placentas obtained from women four years after the exposure had occurred contained several PCB congeners known to be present in the rice oil as well as two toxic PCDF congeners: 2,3,4,7,8-pentachlorodibenzofuran (2,3,4,7,8-PCDF) and 1,2,3,4,7,8-hexachlorodibenzofuran (1,2,3,4,7,8-HCDF). Placentas from exposed women had markedly elevated activities of two cytochrome P1-450 dependent enzymes, arylhydrocarbon hydroxylase and ethoxyresorufin O-deethylase. The average magnitude of enzyme induction was 100-fold, but much interindividual variation was evident. Binding properties of epidermal growth factor (EGF) to its receptor were not altered by PCB-PCDF exposure. However, EGF-stimulated autophosphorylation of the EGF receptor was decreased significantly in placentas from exposed women and this effect was strongly correlated with decreased birth weight. Species comparisons of effects on EGF receptor actions and cytochrome P-450 isoenzymes, coupled with data on tissue concentrations of PCDFs, suggest that humans are more sensitive than rats to some of the biochemical effects of PCDFs and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The data are discussed in relation to key issues in the risk assessment of the toxic halogenated aromatics.