A preliminary operational classification system for nonmutagenic modes of action for carcinogenesis.

This article proposes a system of categories for nonmutagenic modes of action for carcinogenesis. The classification is of modes of action rather than individual carcinogens, because the same compound can affect carcinogenesis in more than one way. Basically, we categorize modes of action as: (1) co-initiation (facilitating the original mutagenic changes in stem and progenitor cells that start the cancer process) (e.g. induction of activating enzymes for other carcinogens); (2) promotion (enhancing the relative growth vs differentiation/death of initiated clones (e.g. inhibition of growth-suppressing cell-cell communication); (3) progression (enhancing the growth, malignancy, or spread of already developed tumors) (e.g. suppression of immune surveillance, hormonally mediated growth stimulation for tumors with appropriate receptors by estrogens); and (4) multiphase (e.g., "epigenetic" silencing of tumor suppressor genes). A priori, agents that act at relatively early stages in the process are expected to manifest greater relative susceptibility in early life, whereas agents that act via later stage modes will tend to show greater susceptibility for exposures later in life.

Use of biological markers and pharmacokinetics in human health risk assessment.

There are two reasons to connect discussions of biological markers and pharmacokinetics. First, both tend to open up the black box between exposure and effect. Doing this promises more complete scientific understanding than simple input-output analysis, the possibility of better mechanism-based projection of risk beyond the range of possible direct observations, and the possibility of greater sensitivity of analysis, in some cases going from the organism to the cell as the unit of analysis. Second, pharmacokinetic (or similar pharmacodynamic) analysis will often be essential for appropriate interpretation of biological marker information. One needs some sort of dynamic model of the generation and loss of the marker in relation to exposure in order to use a biological marker, either to form a better measure of dosage (either accumulated past dose, or biologically relevant dose), or to make an improved prediction of effect. (For example, the use of a blood cadmium level alone to predict kidney effects might be inferior to predictions based on aggregate past accumulation of cadmium in the kidney, based on the past history of cadmium blood levels x time). Several examples will be discussed of the use of biomarkers and pharmacokinetics in risk assessments for both carcinogenesis and other effects.

Needs for public health intervention and needs for new research on vinyl halides and their polymers: a public policy perspective.

Consideration of needs for public health interventions and new research requires comparative assessments of the health benefits that are likely to result from alternative uses of limited regulatory and technical resources. This paper briefly examines regulatory and research priorities in the light of recent information on the carcinogenic hazards of vinyl chloride and alkyl and vinyl halides related to vinyl chloride, the respiratory-system hazards of poly (vinyl chloride), and the reproductive hazards of vinyl chloride. Specific suggestions are made for relatively promising types of efforts in these areas.

The challenge of mechanism-based modeling in risk assessment for neurobehavioral end points.

The mathematical form for a dose-time-response model is ideally not just a convenience for summarizing or fitting a particular data set--it represents a hypothesis. The more this hypothesis reflects a mechanistically sophisticated view of the likely reality, the more it can lead to potentially informative validating or invalidating types of predictions about the results of real experiments and (in the long run) reasonably credible predictions outside the range of direct observations. This paper first reviews some distinctive features of the nervous system and neurotoxic responses and theoretically explores some basic quantitative implications of these features. Relationships are derived for how dose-response relationships for the inhibition of function should depend on the numbers of neurons in series or redundant parallel arrangements that are required or capable of performing the function. Previous work is reviewed in which some less nervous-system-specific features were the foci of quantitative risk-assessment modeling for specific neurotoxic end points. These include a) rates of repair of putatively reversible damage in the case of acrylamide; b) human interindividual variability in susceptibility to fetal/developmental effects in the case of methylmercury; and c) opportunities to use intermediate biomarkers to assist in integrated animal toxicological and epidemiologic investigations of the chronic cumulative risks posed by agents that contribute to neuronal loss with increasing age and pathology.

Risk assessment for neurobehavioral toxicity: SGOMSEC joint report.

Behavioral end points for neurotoxicity risk assessment have been developed and examined over the past three decades. They are now ready to move from simple qualitative guidelines, such as exemplified by reference doses, to more quantitative models, such as benchmark doses, based on dose-response information. Risk assessors, confronted by a wider array of methodologies and data than in the past, should be offered guidance in interpretation because now they have to deal with unaccustomed questions and problems. These include reversibility, susceptible populations, multiple end points, and the details of dose-response and dose-effect distributions.

Human health risks due to consumption of chemically contaminated fishery products.

A small proportion of fishery products contaminated with appreciable amounts of potentially hazardous inorganic and organic contaminants from natural and environmental sources seem to pose the greatest potential for toxicity to consumers of fishery products in the United States. Health risks due to chemicals (e.g., modest changes in the overall risk of cancer, subtle deficits of neurological development in fetuses and children) are difficult to measure directly in people exposed to low levels. Immunocompetence may increase cancer risk. Inferences about the potential magnitude of these problems must be based on the levels of specific chemical present, observations of human populations and experimental animals exposed to relatively high doses, and theories about the likely mechanisms of action of specific intoxicants and the population distribution of sensitivity of human exposure. Lognormal distributions were found to provide good descriptions of the pattern of variation of contaminant concentrations among different species and geographic areas; this variability offers a solution for reduction of exposure through restricting harvest of aquatic animals from certain sites and by excluding certain species. Available information suggest that risks are not generally of high magnitude; nevertheless, their control will significantly improve public health.(ABSTRACT TRUNCATED AT 250 WORDS)

Distributions of individual susceptibility among humans for toxic effects. How much protection does the traditional tenfold factor provide for what fraction of which kinds of chemicals and effects?

A significant data base has been assembled on human variability in parameters representing a series of steps in the pathway from external exposure to the production of biological responses: contact rate (e.g., breathing rates/body weight, fish consumption/body weight); uptake or absorption (mg/kg)/intake or contact rate; general systemic availability net of first pass elimination and dilution; systemic elimination or half-life; active site availability/general systemic availability; physiological parameter change/active site availability; functional reserve capacity--change in baseline physiological parameter needed to pass a criterion of abnormal function or exhibit a response. This paper discusses the current results of analyzing these data to derive estimates for distributions of human susceptibility to different routes of exposure and types of adverse effects. The degree of protection is tentatively evaluated by projecting the incidences of effects that would be expected for a tenfold lowering of exposure from a 5% incidence level if the population distribution of susceptibility were truly log-normal out to the extreme tails, and if the populations, chemicals, and responses that gave rise to the underlying data were representative of the cases to which traditional uncertainty factor is applied. The results indicate that, acting by itself, a tenfold reduction in dose from a 5% effect level is associated with effect incidences ranging from slightly less than one in ten thousand, for a median chemical/response, to a few per thousand, for chemicals and responses that have greater human interindividual variability than 19 out of 20 typical chemicals/responses. In practice, for many of the cases where the traditional tenfold factor is applied, additional protection is provided by other uncertainty factors. Nevertheless, the results generate some reason for concern that current application of traditional safety or uncertainty factor approaches may allow appreciable incidences of responses in some cases.

Human interindividual variability in susceptibility to toxic effects: from annoying detail to a central determinant of risk.

It is unusual to find variability issues as the central focus of a scientific conference. The discussion below first suggests why variability has often been an "annoying detail" in both basic animal toxicology and the human testing of new drugs. Then it gives some reasons why improved quantitative variability information is likely to be important. Better definition of the sources and magnitude of variability in susceptibility in the human population is a central issue for, (1) making more quantitative estimates of both cancer and non-cancer risks from occupational and environmental exposures, and (2) designing protocols for the use of drugs that maximize benefits for the risks incurred in a diverse patient population. Finally, it offers some suggestions about how better variability information is to be obtained and/or extracted from existing information.

Analysis of dose/time/response relationships for chronic toxic effects: the case of acrylamide.

This case study illustrates how a very simple dynamic modeling approach can extract information of interest for both toxic mechanism research and risk assessment from a series of dose/time/response data. The technique is applicable for effects that are thought to result from damage processes that are reversible, at least at low doses and times of exposure. The data sets analyzed provided information on some specific manifestation of acrylamide neurotoxicity produced by different combinations of acrylamide dose rate and duration of exposure. Assuming that responses occur when a specific amount of axonal damage accumulates, and that the repair of damage depends directly on the amount of damage present, the dose-related change in the time required to produce a specific type of effect can be used to estimate: (1) The rate of repair of the incipient damage - and differences in repair rates for different individuals within species, and among different species, and (2) The dose of acrylamide that would be just barely able to produce each effect in each species, if the experiment were conducted over the animal's entire lifespan. Information of the first type may also be helpful in neurotoxicology research. Specific biomarkers for the main process causing a particular response should be repaired in different locations and in different species with the dynamics that are consistent with the repair rates calculated from the dose vs. time-of-effect data.

Exposure efficiency: concept and application to perchloroethylene exposure from dry cleaners.

Standard approaches for computing population exposures due to specific sources of air pollutants are relatively complex. In many cases, more simple and approximate methods would be useful. This paper develops an approach, based on the concept of exposure efficiency, that may be used for estimating the impact of a source (or source class) on the integrated population exposure. The approach is illustrated by an example, which uses the concept of exposure efficiency to examine the impact of perchloroethylene emissions from dry cleaners in the United States. The paper explores the geographic variability of exposure efficiency by evaluating it for each of 100 randomly selected dry cleaners. For perchloroethylene, which has a long atmospheric residence time, the site-to-site variability in exposure efficiency is found to be relatively small. This suggests that simple exposure assessments, based on generic distributional characterizations of exposure efficiency, may be used in risk assessments without introducing appreciable uncertainty. For many compounds, like perchloroethylene, the uncertainty inherent in the estimation of cancer potency or source emissions would dominate these small errors.

Human variability in susceptibility How big, how often, for what responses to what agents?

This paper first reviews in plain language some basic concepts and methods for estimating inter-individual variability in susceptibility from human data. A scale is offered to allow different variability findings to be understood and compared. Then the accumulated results of different variability analyses, information on how much variability has been observed and how often, is summarized in the form of a series of box plots. Data are presented on pharmacodynamic variability for various non-cancer effects, variability in susceptibility to infectious organisms, and variability in susceptibility to carcinogenesis by genetically-acting agents.

Variability in susceptibility - how big, how often, for what responses to what agents?

This paper surveys some recent available observations in humans on interindividual variability in exposure-related parameters, pharmacokinetics, and pharmacodynamics. Overall, I think two inferences are warranted. First, the drug and epidemiological literatures do contain information that can shed new light on the extent of variability in the doses associated with different non-cancer responses. These data are waiting to be systematically extracted and analyzed. Second, I think it is likely that with more systematic measurement and analysis of interindividual variability we are likely to find that there are systematic tendencies for some kinds of responses to some categories of agents to occur at more variable exposures/doses than others. If we gather and analyze additional data of this type, we may be able to recommend adaptive modifications to the ten-fold safety factor tuned to these differences.

Risk evaluation: criteria arising from legal traditions and experience with quantitative risk assessment in the United States.

Making use of quantitative estimates of risk involves sometimes painful choices about risk control options and ethical and social policies for additional control and/or acceptance of remaining risks. Out of the history of these choices in the U.S., we have drawn four broad categories of risk control criteria: The first of these is entirely qualitative; the last three can be informed by different kinds of quantitative analyses. The analyses differ in the implications of variability and uncertainty, among other factors. These suggested criteria should not be seen as a kind of formula to be programmed into a computer in place of human decision making. Rather, we hope they will contribute to an evolving language that can accurately represent our advancing technical understanding of the facts and frankly and compassionately convey our maturing understanding of the relevant value questions.

The use of well-defined biomarkers (such as blood lead) in risk assessment.

Biomarkers have a number of different uses in risk assessment, including (1) a variety of applications as dosimeters, (2) as an aid in quantifying inter-individual variability in susceptibility; and (3) as intermediate effect parameters that can help the analyst predict outcomes that are difficult to measure directly. This paper focuses primarily on applications of the first and second types, which are most frequently found in assessing risks from inorganic compounds.

Pharmacokinetic principles for dose-rate extrapolation of carcinogenic risk from genetically active agents.

Neither experimental animal exposures nor real-life human exposures are delivered at a constant level over a full lifetime. Although there are strong theoretical reasons why all pharmacokinetic processes must "go linear" at the limit of low dose rates, fluctuations in dose rate may produce nonlinearities that either increase or decrease actual risks relative to what would be expected for constant lifetime exposure. This paper discusses quantitative theory and specific examples for a number of processes that can be expected to give rise to pharmacokinetic nonlinearities at high dose rates--including transport processes (e.g., renal tubular secretion), activating and detoxifying metabolism, DNA repair, and enhancement of cell replication following gross toxicity in target tissues. At the extreme, full saturation of a detoxification or DNA repair process has the potential to create as much as a dose dependence of risk on dose delivered in a single burst, and if more than one detoxification step becomes fully saturated, this can be compounded. Effects via changes in cell replication rates, which appear likely to be largely responsible for the steep upward turning curve of formaldehyde carcinogenesis in rats, can be even more profound over a relatively narrow range of dosage. General suggestions are made for experimental methods to detect nonlinearities arising from the various sources in premarket screening programs.

The promise of molecular epidemiology for quantitative risk assessment.

In the long run, molecular epidemiological techniques can provide important insights for understanding a wide variety of important issues in current risk assessment and are applicable across a broad spectrum of adverse effects in addition to carcinogenesis. Unfortunately, current risk assessment practices make very little use of the kind of detailed mechanistic information that molecular epidemiology can provide. Eventually, there is reason to hope that the availability of mechanistic insights provided in part by molecular epidemiology can produce some of the "essential tension" required to reform paradigms for the formulation of quantitative risk assessment models in general.