Rodent toxicity and nongenotoxic carcinogenesis: knowledge-based human risk assessment based on molecular mechanisms.

It is necessary to determine whether chemicals or drugs have the potential to pose a threat to human health. Chemicals that can damage DNA are detected in short-term assays, but the detection of nongenotoxic carcinogens relies upon bioassays in laboratory animals. However, there are marked differences between rodents and humans in response to nongenotoxic carcinogens, which makes the relevance of rodent data to human risk assessment questionable. Here, we address the background issues concerning rodent nongenotoxic carcinogenesis and then focus upon peroxisome proliferators, chloroform, and dioxins as examples of toxicants that cause rodent-specific oxidative stress, cell proliferation, and the suppression of apoptosis. In the case of peroxisome proliferators and dioxins, this response is receptor-mediated. The evidence presented suggests that, at least for some toxicants, the molecular mechanisms of the rodent carcinogenic responses do not operate in humans; this is discussed in the context of human risk assessment. Finally, consideration is given to incorporating mechanism-based information into risk assessment for regulatory purposes.

The paradoxes ofMTBE.

A widely used gasoline additive, methyl tertiary butyl ether (MTBE), has been controversial, in part because of concerns about potential inhalation health effects and more recently because of added concerns about water contamination. Although many of the issues related to MTBE have not been fully resolved, several apparent paradoxes can be discerned, including the fact that something intended to improve air quality is now seen as a threat to water quality. Among the lessons that can be derived from the MTBE experience is the value of a comprehensive understanding of the potential risk-benefit tradeoffs of different fuels and fuel additives.

Biological effects of low-level exposures: a perspective from U.S. EPA scientists.

Biological effects of low-level exposures (BELLE) may be very important in characterizing the potential health risks of environmental pollutants. Before some features of BELLE, such as effects that may be modulated by adaptive or defense mechanisms, can be taken into greater consideration in U.S. Environmental Protection Agency risk assessments, however adequate information on a toxicant's mode of action and answers to other questions are needed.

Comparisons of estimated human body burdens of dioxinlike chemicals and TCDD body burdens in experimentally exposed animals.

Humans are exposed to mixtures of polyhalogenated aromatic hydrocarbons, and the potential health effects of these exposures are uncertain. A subset of this class of compounds produce similar spectra of toxicity in experimental animals as does 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and these chemicals have been classified as "dioxins." In this study, we compared the body burdens of dioxins that produce effects in experimental animals to body burdens associated with these effects in humans. Human body burdens were estimated from lipid-adjusted serum concentrations of dioxins, assuming dioxins are equally distributed in body fat and an adult has 22% body fat. The toxic equivalency factor (TEF) method was used to calculate body burdens of dioxins in humans. These calculations included dibenzo-p-dioxins, dibenzofurans, and polychlorinated biphenyls. In the general population, average background concentrations were estimated at 58 ng TCDD equivalents (TEQ)/kg serum lipid, corresponding to a body burden of 13 ng TEQ/kg body weight. Populations with known exposure to dioxins have body burdens of 96-7,000 ng TEQ/kg body weight. For effects that have been clearly associated with dioxins, such as chloracne and induction of CYP1A1, humans and animals respond at similar body burdens. Induction of cancer in animals occurs at body burdens of 944-137,000 ng TCDD/kg body weight, while noncancer effects in animals occur at body burdens of 10-12,500 ng/kg. Available human data suggest that some individuals may respond to dioxin exposures with cancer and noncancer effects at body burdens within one to two orders of magnitude of those in the general population.

Future directions and research needs.

In this paper, three perspectives for indoor air issues are considered: a) air inside of our homes and offices is a major component of our overall living environment and has potentially great impact on public health; b) there are important scientific questions raised specifically to indoor air that will require skills and expertise to develop and interpret research and data collection efforts; and c) from a risk assessor's point of view, the types and quality of scientific information is critical to the process of health risk assessment to risk managers to make the best decisions regarding environmental risks from indoor air. The primary focus of this presentation is to highlight suggested future directions and needs of the U.S. Environmental Protection Agency that formed the core of a report to Congress on assessment and control of indoor air pollution. The five major areas that constitute the current EPA indoor air research strategy are monitoring/building studies; health effects; source characterization/mitigation; health impact/risk assessment; and program management/technology transfer. Additionally, major trends and research needs are discussed, including greater emphasis on noncancer effects and multiple pollutants at low levels and the need for more sensitive measures for detecting adverse health effects to more effectively characterize chemically sensitive individuals and population subgroups.

The U.S. Environmental Protection Agency's risk assessment guidelines.

This paper has been reviewed by the Office of Health and Environmental Assessment, U.S. Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use. In 1983, the U.S. National Academy of Sciences (U.S. NAS) proposed a framework for the processes of risk assessment and risk management in government agencies (U.S. NAS, 1983). Using the U.S. NAS scheme as an organizing principle, the U.S. Environmental Protection Agency (U.S. EPA) published guidelines pertaining to risk assessment in five areas: estimating exposures, chemical mixtures, mutagenicity, suspect developmental toxicity and carcinogenicity. These guidelines were developed to promote high technical quality and consistent practice of risk assessment Agencywide. This paper will discuss the historical development of the guidelines and their role in the work performed by the Agency. Each of the five (5) guidelines is outlined and anticipated revisions discussed. Related assessment activities and new subject areas are also presented.

The significance of DNA damage and repair mechanisms in health risk assessment.

Clearly, the distinction of the three components in the underlying mechanisms of toxicity--pharmacokinetics, pharmacodynamics, and cell kinetics--is somewhat artificial. Together they form a continuous process rather than a set of stages. But these components correspond to the areas of studies that are often applied to the investigation of toxic mechanisms. Moreover, the components identify complexes of interacting processes, the consequences of which must be studied by examining their actions in concert with one another--metabolic activation must be examined as it competes with excretion, and rates of DNA-adduct formation must be studied along with mechanisms and rates of their repair. By enumerating these components, it becomes evident that clarification of the biological processes in only one realm, say pharmacokinetics, leaves other parts of the "black box" unrevealed. Components that are inadequately understood can be bridged either by plausible assumptions or by empirical measurement, but at the cost of some uncertainty in the risk extrapolations. For some processes, the artificial division into components may be problematic. For example, mutation rates clearly depend not only on the pharmacodynamic processes of creation of DNA adducts and their removal via repair, but also on the rates of cell division, allowing fixing of mutations, and on survival of the affected cells. The extrapolation of toxic effects across dose levels and across species hinges on the changes in the proportionality of input to output in each of the three components. Different degrees of metabolic activation of a procarcinogen across species clearly affect the comparative potency of an agent in experimental animals and human beings.(ABSTRACT TRUNCATED AT 250 WORDS)