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.

Human interindividual variability in susceptibility to airborne particles.

Part of the explanation for the persistent epidemiological findings of associations between mortality and morbidity with relatively modest ambient exposures to airborne particles may be that some people are much more susceptible to particle-induced responses than others. This study assembled a database of quantitative observations of interindividual variability in pharmacokinetic and pharmacodynamic parameters likely to affect particle response. The pharmacodynamic responses studied included data drawn from epidemiologic studies of doses of methacholine, flour dust, and other agents that induce acute changes in lung function. In general, the amount of interindividual variability in several of these pharmacodynamic response parameters was greater than the variability in pharmacokinetic (breathing rate, deposition, and clearance) parameters. Quantitatively the results indicated that human interindividual variability of breathing rates and major pharmacokinetic parameters-total deposition and tracheobronchial clearance-were in the region of Log(GSD) = 0.1 to 0.2 (corresponding to geometric standard deviations of 10(.1)-10(.2) or 1.26-1.58). Deposition to the deep lung (alveolar region) appeared to be somewhat more variable: Log(GSD) of about 0.3 (GSD of about 2). Among pharmacodynamic parameters, changes in FEV1 in response to ozone and metabisulfite (an agent that is said to act primarily on neural receptors in the lung) were in the region of Log(GSD) of 0.2 to 0.4. However, similar responses to methacholine, an agent that acts on smooth muscle, seemed to have still more variability (0.4 to somewhat over 1.0, depending on the type of population studied). Similarly high values were suggested for particulate allergens. Central estimates of this kind of variability, and the close correspondence of the data to lognormal distributions, indicate that 99.9th percentile individuals are likely to respond at doses that are 150 to 450-fold less than would be needed in median individuals. It seems plausible that acute responses with this amount of variability could form part of the mechanistic basis for epidemiological observations of enhanced mortality in relation to ambient exposures to fine particles.

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 interindividual variability in parameters related to health risks.

This paper reviews existing data on the variability in parameters relevant for health risk analyses. We cover both exposure-related parameters and parameters related to individual susceptibility to toxicity. The toxicity/susceptibility data base under construction is part of a longer term research effort to lay the groundwork for quantitative distributional analyses of non-cancer toxic risks. These data are broken down into a variety of parameter types that encompass different portions of the pathway from external exposure to the production of biological responses. The discrete steps in this pathway, as we now conceive them, are: Contact Rate (Breathing rates per body weight; fish consumption per body weight) Uptake or Absorption as a Fraction of Intake or Contact Rate General Systemic Availability Net of First Pass Elimination and Dilution via Distribution Volume (e.g., initial blood concentration per mg/kg of uptake) Systemic Elimination (half life or clearance) Active Site Concentration per Systemic Blood or Plasma Concentration Physiological Parameter Change per Active Site Concentration (expressed as the dose required to make a given percentage change in different people, or the dose required to achieve some proportion of an individual's maximum response to the drug or toxicant) Functional Reserve Capacity-Change in Baseline Physiological Parameter Needed to Produce a Biological Response or Pass a Criterion of Abnormal Function Comparison of the amounts of variability observed for the different parameter types suggests that appreciable variability is associated with the final step in the process-differences among people in "functional reserve capacity." This has the implication that relevant information for estimating effective toxic susceptibility distributions may be gleaned by direct studies of the population distributions of key physiological parameters in people that are not exposed to the environmental and occupational toxicants that are thought to perturb those parameters. This is illustrated with some recent observations of the population distributions of Low Density Lipoprotein Cholesterol from the second and third National Health and Nutrition Examination Surveys.

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.

Variability in PAH-DNA adduct measurements in peripheral mononuclear cells: implications for quantitative cancer risk assessment.

Biomarkers such as DNA adducts have significant potential to improve quantitative risk assessment by characterizing individual differences in metabolism of genotoxins and DNA repair and accounting for some of the factors that could affect interindividual variation in cancer risk. Inherent uncertainty in laboratory measurements and within-person variability of DNA adduct levels over time are putatively unrelated to cancer risk and should be subtracted from observed variation to better estimate interindividual variability of response to carcinogen exposure. A total of 41 volunteers, both smokers and nonsmokers, were asked to provide a peripheral blood sample every 3 weeks for several months in order to specifically assess intraindividual variability of polycyclic aromatic hydrocarbon (PAH)-DNA adduct levels. The intraindividual variance in PAH-DNA adduct levels, together with measurement uncertainty (laboratory variability and unaccounted for differences in exposure), constituted roughly 30% of the overall variance. An estimated 70% of the total variance was contributed by interindividual variability and is probably representative of the true biologic variability of response to carcinogenic exposure in lymphocytes. The estimated interindividual variability in DNA damage after subtracting intraindividual variability and measurement uncertainty was 24-fold. Inter-individual variance was higher (52-fold) in persons who constitutively lack the Glutathione S-Transferase M1 (GSTM1) gene which is important in the detoxification pathway of PAH. Risk assessment models that do not consider the variability of susceptibility to DNA damage following carcinogen exposure may underestimate risks to the general population, especially for those people who are most vulnerable.

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.

Comparison of contact site cancer potency across dose routes: case study with epichlorohydrin.

Risk assessment for airborne carcinogens is often limited by a lack of inhalation bioassay data. While extrapolation from oral-based cancer potency factors may be possible for some agents, this is not considered feasible for contact site carcinogens. The change in contact sites (oral: g.i. tract; inhalation: respiratory tract) when switching dose routes leads to possible differences in tissue sensitivity as well as chemical delivery. This research evaluates the feasibility to extrapolate across dose routes for a contact site carcinogen through a case study with epichlorohydrin (EPI). EPI cancer potency at contact sites is compared across three bioassays involving different dose routes (gavage, drinking water, inhalation) through the use of dosimetry models to adjust for EPI delivery to contact sites. Results indicate a large disparity (two orders of magnitude) in potency across the three routes of administration when expressed as the externally applied dose. However, when expressed as peak delivered dose, inhalation and oral potency estimates are similar and overall, the three potency estimates are within a factor of seven. The results suggest that contact site response to EPI is more dependent upon the rate than the route of delivery, with peak concentration the best way to extrapolate across dose routes. These results cannot be projected to other carcinogens without further study.

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.

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.

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 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.

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.

Human interindividual variability--a major source of uncertainty in assessing risks for noncancer health effects.

For noncancer effects, the degree of human interindividual variability plays a central role in determining the risk that can be expected at low exposures. This discussion reviews available data on observations of interindividual variability in (a) breathing rates, based on observations in British coal miners; (b) systemic pharmacokinetic parameters, based on studies of a number of drugs; (c) susceptibility to neurological effects from fetal exposure to methyl mercury, based on observations of the incidence of effects in relation to hair mercury levels; and (d) chronic lung function changes in relation to long-term exposure to cigarette smoke. The quantitative ranges of predictions that follow from uncertainties in estimates of interindividual variability in susceptibility are illustrated.

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.

Uncertainties in pharmacokinetic modeling for perchloroethylene: II. Comparison of model predictions with data for a variety of different parameters.

In this paper we compare expectations derived from 10 different human physiologically based pharmacokinetic models for perchloroethylene with data on absorption via inhalation, and concentrations in alveolar air and venous blood. Our most interesting finding is that essentially all of the models show a time pattern of departures of predictions of air and blood levels relative to experimental data that might be corrected by more sophisticated model structures incorporating either (a) heterogeneity of the fat compartment (with respect to either perfusion or partition coefficients or both) or (b) intertissue diffusion of perchloroethylene between the fat and muscle/VRG groups. Similar types of corrections have recently been proposed to reduce analogous anomalies in the fits of pharmacokinetic models to the data for several volatile anesthetics. A second finding is that models incorporating resting values for alveolar ventilation in the region of 5.4 L/min seemed to be most compatible with the most reliable set of perchloroethylene uptake data.

Risk assessment and management of chemical contaminants in fishery products consumed in the USA.

In the USA a small proportion of fishery products are contaminated with appreciable amounts of potentially hazardous contaminants. However, risks to consumers are not generally high. Inorganic contaminants with the greatest potential for toxicity are antimony, arsenic, cadmium, lead, mercury, selenium and sulfites. Among organic compounds, polychlorinated biphenyls, dioxins, several chlorinated hydrocarbon insecticides, certain processing-related and aquaculture-related contaminants pose potential risks for consumers. Log-normal distributions appear to provide good descriptions of the pattern of variation of contaminant concentrations among different geographic areas, and some contaminants (mostly organic) appear to be much more variable than others. This variability offers a solution for reduction of exposure through restricting the harvest of aquatic organisms from specific sites, and by excluding certain species. It is recommended that: (i) existing State and Federal regulations and environmental monitoring be strengthened and enforced to minimize contamination of the aquatic environment; (ii) a program of shared responsibility be instituted, where Federal agencies develop a set of monitoring and inspection practices and state agencies assume responsibility for primary control, site closures and advisories issue; (iii) research and public education by government agencies and health professionals be expanded to determine actual risks and approaches to manage them; (iv) mandatory labeling be considered for specific contaminants; (v) a better system requiring international agreements be developed in order to minimize the differences among various national regulatory approaches.

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)