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D Hattis

Publications and source records attributed to D Hattis.

At least 19 recordsLinked to original sources
PubMed2001

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.

Air Pollutants↗
PubMed2000

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.

Carcinogens↗
PubMed1999

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.

Analysis of Variance↗
PubMed1999

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.

Biological Availability↗
PubMed1997

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.

Adult↗
PubMed1996

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.

Animals↗
PubMed1996

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.

Animals↗
PubMed1996

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.

Behavior↗
PubMed1994

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.

Disease Susceptibility↗
PubMed1993

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.

Biological Transport, Active↗
PubMed1993

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)

Eating↗
PubMed1991

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.

Biomarkers↗
PubMed1990

Strategies for testing the "irritation-signaling" model for chronic lung effects of fine acid particles.

The "irritation signaling" model proposed that a long term contribution to chronic bronchitis might result from the repeated delivery of "signals" resulting from temporary localized acidification of the bronchial epithelium by the action of individual particles. This led to a prediction that the effectiveness of particles in inducing changes in mucus secreting cell numbers/types should depend on the number of particles deposited that contained a particular amount of acid--implying that particles below a certain size cutoff (and therefore lacking a minimum amount of acid) should be ineffective; and that particle potency per unit weight should be greatest at the cutoff and decline strongly above the cutoff. Since the development of this hypothesis both epidemiological observations and some experimental studies have tended to reinforce the notion that acid particles can make a contribution to relatively long lasting bronchitic-like changes, and enhance the desirability of more direct testing of the model. In this paper we develop a general theoretical framework for the contributions of environmental agents to chronic obstructive lung disease, and a series of alternative hypotheses against which the predictions of the "irritant signaling" model can be compared. Based on this, we suggest a research program that could be used to further develop and test the model and reasonable alternatives.

Acids↗
PubMed1990

Uncertainties in pharmacokinetic modeling for perchloroethylene. I. Comparison of model structure, parameters, and predictions for low-dose metabolism rates for models derived by different authors.

In recent years physiologically based pharmacokinetic models have come to play an increasingly important role in risk assessment for carcinogens. The hope is that they can help open the black box between external exposure and carcinogenic effects to experimental observations, and improve both high-dose to low-dose and interspecies projections of risk. However, to date, there have been only relatively preliminary efforts to assess the uncertainties in current modeling results. In this paper we compare the physiologically based pharmacokinetic models (and model predictions of risk-related overall metabolism) that have been produced by seven different sets of authors for perchloroethylene (tetrachloroethylene). The most striking conclusion from the data is that most of the differences in risk-related model predictions are attributable to the choice of the data sets used for calibrating the metabolic parameters. Second, it is clear that the bottom-line differences among the model predictions are appreciable. Overall, the ratios of low-dose human to bioassay rodent metabolism spanned a 30-fold range for the six available human/rat comparisons, and the seven predicted ratios of low-dose human to bioassay mouse metabolism spanned a 13-fold range. (The greater range for the rat/human comparison is attributable to a structural assumption by one author group of competing linear and saturable pathways, and their conclusion that the dangerous saturable pathway constitutes a minor fraction of metabolism in rats.) It is clear that there are a number of opportunities for modelers to make different choices of model structure, interpretive assumptions, and calibrating data in the process of constructing pharmacokinetic models for use in estimating "delivered" or "biologically effective" dose for carcinogenesis risk assessments. We believe that in presenting the results of such modeling studies, it is important for researchers to explore the results of alternative, reasonably likely approaches for interpreting the available data--and either show that any conclusions they make are relatively insensitive to particular interpretive choices, or to acknowledge the differences in conclusions that would result from plausible alternative views of the world.

Animals↗
PubMed1990

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.

Animals↗