Environmental Tobacco Smoke: Exposure-Response Relationships in Epidemiologic Studies

Demonstration of a dose-response relationship for environmental tobacco smoke (ETS) is an important indication of causality. Central to the analysis and interpretation of dose-response relations as described in epidemiological studies is the relationship between dose and exposure. It must be recognized that in studies of ETS we have only surrogate measures of dose, and these surrogate measures (based on exposure) are imperfect. The question-based measures of ETS exposure generally have not been standardized, may have limited validity and reliability, and cannot comprehensively describe total ETS exposure, exposure to individual ETS components, nor doses of biologically relevant agents at target sites. Nevertheless, useful data have been yielded in epidemiologic studies linking ETS exposure to increased respiratory infection and symptoms, reduced lung growth in children, and increased lung cancer in nonsmoking adults. The more consistent exposure-response data for studies on acute health in children may reflect the greater difficulty in measuring exposure in studies of chronic health in adults.     

Distribution of Exposure Concentrations and Doses for Constituents of Environmental Tobacco Smoke

The ultimate goal of the research reported in this series of three articles is to derive distributions of doses of selected environmental tobacco smoke (ETS)-related chemicals for nonsmoking workers. This analysis uses data from the 16-City Study collected with personal monitors over the course of one workday in workplaces where smoking occurred. In this article, we describe distributions of ETS chemical concentrations and the characteristics of those distributions (e.g., whether the distribution was log normal for a given constituent) for the workplace exposure. Next, we present population parameters relevant for estimating dose distributions and the methods used for estimating those dose distributions. Finally, we derive distributions of doses of selected ETS-related constituents obtained in the workplace for people in smoking work environments. Estimating dose distributions provided information beyond the usual point estimate of dose and showed that the preponderance of individuals exposed to ETS in the workplace were exposed at the low end of the dose distribution curve. The results of this analysis include estimations of hourly maxima and time-weighted average (TWA) doses of nicotine from workplace exposures to ETS (extrapolated from 1 day to 1 week) and doses derived from modeled lung burdens of ultraviolet-absorbing particulate matter (UVPM) and solanesol resulting from workplace exposures to ETS (extrapolated from 1 day to 1 year).     

Assessing Exposures to Environmental Tobacco Smoke

The combustion of tobacco indoors results in the emission of a wide range of air contaminants that are associated with a variety of acute and chronic health and comfort effects. Exposures to environmental tobacco smoke (ETS) are assessed for epidemiologic studies and risk assessment and risk management applications. An individual's or population's exposure to ETS can be assessed by direct methods, which employ personal air monitoring and biomarkers, and indirect methods, which utilize various degrees of microenvironmental measurements of spaces, models, and questionnaires in combination with time-activity information. The major issues related to assessing exposures to ETS are summarized and discussed, including the physical-chemical nature of ETS air contaminants, use of proxy air contaminants to represent ETS, use of biomarkers, models for estimating ETS concentrations indoors, and the application of questionnaires.     

Exposure to Environmental Tobacco Smoke in the Workplace and the Impact of Away-From-Work Exposure

Concentrating on exposure in workplaces where smoking occurs, we examined environmental tobacco smoke (ETS)-related concentration data from the 16-City Study.^(1,2) This study involved a large population of nonsmokers, used personal monitors, and encompassed a wide selection of ETS-related constituents. This first article in a series of three describes the 16-City Study, considers the impact of demographic variables, and concludes that these variables did not explain differences in exposure to ETS. We compared 16-City Study concentrations obtained in the workplace to previously reported workplace concentrations and determined that data from this study were representative of current ETS exposure in nonmanufacturing workplaces where smoking occurs. Considering factors other than demographic factors, we found that, not surprisingly, the number of cigarettes observed in the workplace had an impact on exposure concentrations. Finally, we compared people from homes where smoking occurs with people from nonsmoking homes and found that people from smoking homes observed more smoking in the workplace and experienced higher concentrations of ETS-related compounds in the workplace, even when they observed the same number of cigarettes being smoked in the workplace. In two subsequent articles in this series, we discuss relationships between various ETS markers and provide estimates of distributions of doses to nonsmoking workers employed in workplaces where smoking occurs.     

Assessment of the Effect of Population and Diary Sampling Methods on Estimation of School‐Age Children Exposure to Fine Particles

Population and diary sampling methods are employed in exposure models to sample simulated individuals and their daily activity on each simulation day. Different sampling methods may lead to variations in estimated human exposure. In this study, two population sampling methods (stratified‐random and random‐random) and three diary sampling methods (random resampling, diversity and autocorrelation, and Markov‐chain cluster [MCC]) are evaluated. Their impacts on estimated children's exposure to ambient fine particulate matter (PM_2.5) are quantified via case studies for children in Wake County, NC for July 2002. The estimated mean daily average exposure is 12.9 μg/m³ for simulated children using the stratified population sampling method, and 12.2 μg/m³ using the random sampling method. These minor differences are caused by the random sampling among ages within census tracts. Among the three diary sampling methods, there are differences in the estimated number of individuals with multiple days of exposures exceeding a benchmark of concern of 25 μg/m³ due to differences in how multiday longitudinal diaries are estimated. The MCC method is relatively more conservative. In case studies evaluated here, the MCC method led to 10% higher estimation of the number of individuals with repeated exposures exceeding the benchmark. The comparisons help to identify and contrast the capabilities of each method and to offer insight regarding implications of method choice. Exposure simulation results are robust to the two population sampling methods evaluated, and are sensitive to the choice of method for simulating longitudinal diaries, particularly when analyzing results for specific microenvironments or for exposures exceeding a benchmark of concern.     

Use of Environmental Tobacco Smoke Constituents as Markers for Exposure

The 16-City Study analyzed for gas-phase environmental tobacco smoke (ETS) constituents (nicotine, 3-ethenyl pyridine [3-EP], and myosmine) and for particulate-phase constituents (respirable particulate matter [RSP], ultraviolet-absorbing particulate matter [UVPM], fluorescing particulate matter [FPM], scopoletin, and solanesol). In this second of three articles, we discuss the merits of each constituent as a marker for ETS and report pair-wise comparisons of the markers. Neither nicotine nor UVPM were good predictors for RSP. However, nicotine and UVPM were good qualitative predictors of each other. Nicotine was correlated with other gas-phase constituents. Comparisons between UVPM and other particulate-phase constituents were performed. Its relation with FPM was excellent, with UVPM approximately 1 1/2 times FPM. The correlation between UVPM and solanesol was good, but the relationship between the two was not linear. The relation between UVPM and scopoletin was not good, largely because of noise in the scopoletin measures around its limit of detection. We considered the relation between nicotine and saliva cotinine, a metabolite of nicotine. The two were highly correlated on the group level. That is, for each cell (smoking home and work, smoking home but nonsmoking work, and so forth), there was high correlation between average cotinine and 24-hour time-weighted average (TWA) nicotine concentrations. However, on the individual level, the correlations, although significant, were not biologically meaningful. A consideration of cotinine and nicotine or 3-EP on a subset of the study whose only exposure to ETS was exclusively at work or exclusively at home showed that home exposure was a more important source of ETS than work exposure.     

Estimating Benchmark Exposure for Air Particulate Matter Using Latent Class Models

We performed benchmark exposure (BME) calculations for particulate matter when multiple dichotomous outcome variables are involved using latent class modeling techniques and generated separate results for both the extra risk and additional risk. The use of latent class models in this study is advantageous because it combined several outcomes into just two classes (namely, a high‐risk class and a low‐risk class) and compared these two classes to obtain the BME levels. This novel approach addresses a key problem in risk estimation—namely, the multiple comparisons problem, where separate regression models are fitted for each outcome variable and the reference exposure will rely on the results of the best‐fitting model. Because of the complex nature of the estimation process, the bootstrap approach was used to estimate the reference exposure level, thereby reducing uncertainty in the obtained values. The methodology developed in this article was applied to environmental data by identifying unmeasured class membership (e.g., morbidity vs. no morbidity class) among infants in utero using observed characteristics that included low birth weight, preterm birth, and small for gestational age.     

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 RateGeneral 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 ConcentrationPhysiological 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 FunctionComparison 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.     

An Exploratory Study of Variations in Exposure to Environmental Tobacco Smoke in the United States

There is considerable interest in assessing exposure to environmental tobacco smoke (ETS) and in understanding the factors that affect exposure at various venues. The impact of these complex factors can be researched only if monitoring studies are carefully designed. Prior work by Jenkins et al. gathered personal monitor and diary data from 1,564 nonsmokers in 16 metropolitan areas of the United States and compared workplace exposures to ETS with exposures away from work. In this study, these data were probed further to examine (1) the correspondence between work and away-from-work exposure concentrations of ETS; (2) the variability in exposure concentration levels across cities; and (3) the association of ETS exposure concentrations with select socioeconomic, occupation, and lifestyle variables. The results indicate (1) at the population level, there was a positive association between ETS concentrations at the work and away-from-work environments; (2) exposure concentration levels across the 16 cities under consideration were highly variable; and (3) exposure concentration levels were significantly associated with occupation, education, household income, age, and dietary factors. Workplace smoking restrictions were associated with low ETS concentration levels at work as well as away from work. Generally, the same cities that exhibited either lower or higher away-from-work exposure concentration levels also showed lower or higher work exposure concentration levels. The observations suggest that similar avoidance characteristics as well as socioeconomic and other lifestyle factors that affect exposure to ETS may have been in operation in both away-from-work and work settings.     

Modeling the Modification of the Risk of Radon-Induced Lung Cancer by Environmental Tobacco Smoke

The presence of environmental tobacco smoke (ETS) in homes has been implicated in the causation of lung cancer. While of interest in its own right, ETS also influences the risk imposed by radon and its decay products. The interaction between radon progeny and ETS alters the exposure, intake, uptake, biokinetics, dosimetry, and radiobiology of those progeny. The present paper details model predictions of the various influences of ETS on these factors in the U.S. population and provides estimates of the resulting change in the risk from average levels of radon progeny. It is predicted that the presence of ETS produces a very small (perhaps unmeasurable) increase in the risk of radiation-induced tracheobronchial cancer in homes with initially very high particle concentrations for both active and never-smokers, but significantly lowers the risk in homes with initially lower particle concentrations for both groups when generation 4 of the lung is considered the target site. For generation 16, the presence of ETS generally increases the radon-induced risk of lung cancer, although the increase should be unmeasurable at high initial particle concentrations. The net effect of ETS on human health is suggested to be a complicated function of the initial housing conditions, the concentration of particles introduced by smoking, the target generation considered, and the smoking status of exposed populations. This situation precludes any simple statements concerning the role of ETS in governing the incidence of lung cancer in a population.     

Integrating Uncertainty and Interindividual Variability in Environmental Risk Assessment

An integrated, quantitative approach to incorporating both uncertainty and interindividual variability into risk prediction models is described. Individual risk R is treated as a variable distributed in both an uncertainty dimension and a variability dimension, whereas population risk I (the number of additional cases caused by R) is purely uncertain. I is shown to follow a compound Poisson-binomial distribution, which in low-level risk contexts can often be approximated well by a corresponding compound Poisson distribution. The proposed analytic framework is illustrated with an application to cancer risk assessment for a California population exposed to 1,2-dibromo-3-chloropropane from ground water.     

An Enforceable Indoor Air Quality Standard for Environmental Tobacco Smoke in the Workplace1

Environmental tobacco smoke (ETS)has recently been determined by U.S. environmental and occupational health authorities to be a human carcinogen. We develop a model which permits using atmospheric nicotine measurements to estimate nonsmokers’ETS lung cancer risks in individual workplaces for the first time. We estimate that during the 1980s, the U.S. nonsmoking adult population's median nicotine lung exposure (homes and workplaces combined)was 143 micrograms (μg)of nicotine daily, and that most-exposed adult nonsmokers inhaled 1430 μg/day. These exposure estimates are validated by pharmacokinetic modeling which yields the corresponding steady-state dose of the nicotine metabolite, cotinine. For U.S. adult nonsmokers of working age, we estimate median cotinine values of about 1.0 nanogram per milliliter (ng/ml)in plasma, and 6.2 ng/ml in urine; for most-exposed nonsmokers, we estimate cotinine concentrations of about 10 ng/ml in plasma and 62 ng/ml in urine. These values are consistent to within 15% of the cotinine values observed in contemporaneous clinical epidemiological studies. Corresponding median risk from ETS exposure in U.S. nonsmokers during the 1980s is estimated at about two lung cancer deaths (LCDs)per 1000 at risk, and for most-exposed nonsmokers, about two LCDs per 100. Risks abroad appear similar. Modeling of the lung cancer mortality risk from passive smoking suggests that de minimis [i.e., “acceptable” (10^-6)], risk occurs at an 8-hr time-weighted-average exposure concentration of 7.5 nanograms of ETS nicotine per cubic meter of workplace air for a working lifetime of 40 years. This model is based upon a linear exposure-response relationship validated by physical, clinical, and epidemiological data. From available data, it appears that workplaces without effective smoking policies considerably exceed this de minimis risk standard. For a substantial fraction of the 59 million nonsmoking workers in the U.S., current workplace exposure to ETS also appears to pose risks exceeding the de manifestos risk level above which carcinogens are strictly regulated by the federal government.     

Environmental Tobacco Smoke Revisited: The Reliability of the Data Used for Risk Assessment

Several epidemiological studies have found a weak, but consistent association between lung cancer in nonsmokers and exposure to environmental tobacco smoke (ETS). In addition, a purported link between such exposure and coronary heart disease (CHD) has been of major concern. Although it is biologically plausible that ETS has a contributory role in the induction of lung cancer in nonsmoking individuals, dose-response extrapolation-supported by the more solid database for active smokers-gives an additional risk for lung cancer risk that is more than one order of magnitude lower than that indicated by major positive epidemiological studies. The discrepancy between available epidemiological data and dosimetric estimates seems, to a major part, to reflect certain systematic biases in the former that are difficult to control by statistical analysis when dealing with risks of such low magnitudes. These include, most importantly, misclassification of smoking status, followed by inappropriate selection of controls, as well as certain confounding factors mainly related to lifestyle, and possibly also hereditary disposition. A significant part of an association between lung cancer and exposure to ETS would disappear, if, on the average, 1 patient out of 20 nonsmoking cases had failed to tell the interviewer that he had, in fact, recently stopped smoking. In the large International Agency for Research on Cancer (IARC) multicenter study even lower misclassification rates would abolish the weak, statistically nonsignificant associations that were found. In the former study an apparent significant protective effect from exposure to ETS in childhood with respect to lung cancer later in life was reported, a most surprising finding. The fact that the mutation spectrum of the p53 tumor suppressor gene in lung tumors of ETS-exposed nonsmokers generally differs from that found in tumors of active smokers lends additional support to the notion that the majority of tumors found in ETS-exposed nonsmokers have nothing to do with tobacco smoke. The one-sided preoccupation with ETS as a causative factor of lung cancer in nonsmokers may seriously hinder the elucidation of the multifactorial etiology of these tumors. Due to the high prevalence of cardiovascular disease in the population, even a modest causal association with ETS would, if valid, constitute a serious public health problem. By pooling data from 20 published studies on ETS and heart disease, some of which reported higher risks than is known to be caused by active smoking, a statistically significant association with spousal smoking is obtained. However, in most of these studies, many of the most common confounding risk factors were ignored and there appears to be insufficient evidence to support an association between exposure to ETS and CHD. Further, it seems highly improbable that exposure to a concentration of tobacco smoke at a level that is generally much less than 1% of that inhaled by a smoker could result in an excess risk for CHD that-as has been claimed-is some 30% to 50% of that found in active smokers. There are certainly valid reasons to limit exposure to ETS as well as to other air pollutants in places such as offices and homes in order to improve indoor air quality. This goal can be achieved, however, without the introduction of an extremist legislation based on a negligible risk of lung cancer as well as an unsupported and highly hypothetical risk for CHD.     

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.     

Uncertainty and Variability in Health-Related Damages from Coal-Fired Power Plants in the United States

The health‐related damages associated with emissions from coal‐fired power plants can vary greatly across facilities as a function of plant, site, and population characteristics, but the degree of variability and the contributing factors have not been formally evaluated. In this study, we modeled the monetized damages associated with 407 coal‐fired power plants in the United States, focusing on premature mortality from fine particulate matter (PM_2.5). We applied a reduced‐form chemistry‐transport model accounting for primary PM_2.5 emissions and the influence of sulfur dioxide (SO₂) and nitrogen oxide (NO_x) emissions on secondary particulate formation. Outputs were linked with a concentration‐response function for PM_2.5‐related mortality that incorporated nonlinearities and model uncertainty. We valued mortality with a value of statistical life approach, characterizing and propagating uncertainties in all model elements. At the median of the plant‐specific uncertainty distributions, damages across plants ranged from $30,000 to $500,000 per ton of PM_2.5, $6,000 to $50,000 per ton of SO₂, $500 to $15,000 per ton of NO_x, and $0.02 to $1.57 per kilowatt‐hour of electricity generated. Variability in damages per ton of emissions was almost entirely explained by population exposure per unit emissions (intake fraction), which itself was related to atmospheric conditions and the population size at various distances from the power plant. Variability in damages per kilowatt‐hour was highly correlated with SO₂ emissions, related to fuel and control technology characteristics, but was also correlated with atmospheric conditions and population size at various distances. Our findings emphasize that control strategies that consider variability in damages across facilities would yield more efficient outcomes.     

Estimation of the Leukemia Risk in Human Populations Exposed to Benzene from Tobacco Smoke Using Epidemiological Data

Several epidemiological studies have demonstrated an association between occupational benzene exposure and increased leukemia risk, in particular acute myeloid leukemia (AML). However, there is still uncertainty as to the risk to the general population from exposure to lower environmental levels of benzene. To estimate the excess risk of leukemia from low‐dose benzene exposure, various methods for incorporating epidemiological data in quantitative risk assessment were utilized. Tobacco smoke was identified as one of the main potential sources of benzene exposure and was the focus of this exposure assessment, allowing further investigation of the role of benzene in smoking‐induced leukemia. Potency estimates for benzene were generated from individual occupational studies and meta‐analysis data, and an exposure assessment for two smoking subgroups (light and heavy smokers) carried out. Subsequently, various techniques, including life‐table analysis, were then used to evaluate both the excess lifetime risk and the contribution of benzene to smoking‐induced leukemia and AML. The excess lifetime risk for smokers was estimated at between two and six additional leukemia deaths in 10,000 and one to three additional AML deaths in 10,000. The contribution of benzene to smoking‐induced leukemia was estimated at between 9% and 24% (U_pperCL 14–31%). For AML this contribution was estimated as 11–30% (U_pperCL 22–60%). From the assessments carried out here, it appears there is an increased risk of leukemia from low‐level exposure to benzene and that benzene may contribute up to a third of smoking‐induced leukemia. Comparable results from using methods with varying degrees of complexity were generated.     

An Empirical Bayes Approach to Estimating the Relation of Mortality to Exposure to Particulate Matter

As part of its assessment of the health risks associated with exposure to particulate matter (PM), the U.S. Environmental Protection Agency analyzed the risks associated with current levels, and the risk reductions that might be achieved by attainment of alternative PM standards, in two locations in the United States, Philadelphia, and Los Angeles. The concentration-response function describing the relation between a health endpoint and ambient PM concentrations is an important component, and a source of substantial uncertainty, in such risk analyses. In the absence of location-specific estimates, the concentration-response functions necessary for risk assessments in Philadelphia and Los Angeles must be inferred from the available information in other locations. Although the functional form of the concentration-response relations is assumed to be the same everywhere, the value of the PM coefficient in that function may vary from one location to another. Under this model, a distribution describes the probability that the PM coefficient in a randomly selected location will lie in any range of interest. An empirical Bayes estimation technique was used to improve the estimation of location-specific concentration-response functions relating mortality to short-term exposure to particles of aerodynamic diameter less than or equal to 2.5 microm (PM-2.5), for which functions have previously been estimated in several locations. The empirical Bayes-adjusted parameter values and their SEs were used to derive an estimate of the distribution of PM-2.5 coefficients for mortality associated with short-term exposures. From this distribution, distributions of relative risks corresponding to different specified changes in PM-2.5 concentrations could be derived.     

The Interplay of Science, Values, and Experiences Among Scientists Asked to Evaluate the Hazards of Dioxin, Radon, and Environmental Tobacco Smoke

To investigate the extent to which personal values and experiences among scientists might affect their assessment of risks from dioxin, radon, and environmental tobacco smoke (ETS), we conducted an experiment through a telephone survey of 1461 epidemiologists, toxicologists, physicians, and general scientists. Each participant was read a vignette designed to reflect the mainstream scientific thinking on one of the three substances. For half of the participants (group A) the substance was named. For the other half (group B), the substance was not named but was identified only as Substance X, Y, or Z. Knowing the name of the substance had little effect on the scientists' evaluation of dioxin, although those who knew the substance to be dioxin were more likely to rate the substance as a serious environmental health hazard (51% vs. 42%, p = 0.062). For radon, those who knew the substance by name were significantly more likely to consider it an environmental health hazard than were those who knew it as substance Z (91% vs. 78%, p less than 0.001). Participants who knew they were being asked about ETS rather than substance X were significantly more likely to consider the substance an environmental health hazard (88% vs. 66%, p less than 0.001), to consider the substance a serious environmental health hazard (70% vs. 33%, p less than 0.001), to believe that background exposure required public health intervention (85% vs. 41%, p less than 0.001), and to believe that above-background exposure required public health intervention (90% vs. 74%, p less than 0.001). These findings suggest that values and experiences may be influencing health risk assessments for these substances, and indicate the need for more study of this phenomenon.     

Modeling Human Interindividual Variability in Metabolism and Risk: The Example of 4-Aminobiphenyl

We investigate, through modeling, the impact of interindividual heterogeneity in the metabolism of 4-aminobiphenyl (ABP) and in physiological factors on human cancer risk: A physiological pharmacokinetic model was used to quantify the time course of the formation of the proximate carcinogen, N-hydroxy-4-ABP and the DNA-binding of the active species in the bladder. The metabolic and physiologic model parameters were randomly varied, via Monte Carlo simulations, to reproduce interindividual variability. The sampling means for most parameters were scaled from values developed by Kadlubar et al. (Cancer Res., 51 : 4371, 1991) for dogs; variances were obtained primarily from published human data (e.g., measurements of ABP N-oxidation, and arylamine N-acetylation in human liver tissue). In 500 simulations, theoretically representing 500 humans, DNA-adduct levels in the bladder of the most susceptible individuals are ten thousand times higher than for the least susceptible, and the 5th and 95th percentiles differ by a factor of 160. DNA binding for the most susceptible individual (with low urine pH, low N-acetylation and high N-oxidation activities) is theoretically one million-fold higher than for the least susceptible (with high urine pH, high N-acetylation and low N-oxidation activities). The simulations also suggest that the four factors contributing most significantly to interindividual differences in DNA-binding of ABP in human bladder are urine pH, ABP N-oxidation, ABP N-acetylation and urination frequency.