Non-cancer Effects Research Articles

Respiratory health effects of exposure to environmental tobacco smoke.

During the last 25 years, several hundred papers have been published on the respiratory health effects of environmental tobacco smoke (ETS). Various independent assessments have concluded that ETS causes lung cancer in adult nonsmokers and increases the risk of various noncancer effects, principally in children. The effects on children include pneumonia, bronchitis and bronchiolitis in young children; chronic middle ear effusion; increased frequency and severity of attacks among asthmatics; possible induction of asthma in previously asymptomatic individuals; small reductions in lung function; and symptoms of upper respiratory tract irritation. In nonsmoking adults, ETS exposure is associated with irritation of the eyes, nose, and throat, and with wheezing, symptoms of bronchitis, shortness of breath, and decreased lung function. The results of recent studies not only confirm and strengthen the above findings but also provide strong suggestive evidence that ETS causes sinonasal cancer and is a risk factor for sudden infant death syndrome. To mitigate such a preventable environmental health impact, public health measures to reduce involuntary ETS exposure are warranted.

Health risk assessment for toxic emissions from a manufacturing facility

This paper presents the risk associated with the release of toxic chemicals from a manufacturing facility, following the State of California's approach to risk assessment. The facility emits five toxic substances from eight stacks. The building downwash is considered during dispersion calculations. The zone of impact, identified using a risk criteria (i.e. excess cancer risk of 10 in a million), is located in the southeast quandrant from the plant. The size of the impact area is 3.3 km(2). The cancer and non-cancer effects are considered for chromium (VI), benzene, formaldehyde, gasoline vapors, methylene chloride, and selenium using the California Air Pollution Control Officers Association Guidelines. No significant non-cancer effects are found due to the emissions. The maximum calculated risk is 1.197×10(-5) and is an extremely conservative value. Analysis shows that the use of realistic assumptions for exposure duration and unit risk factors during the risk calculations could reduce the zone of impact to 0 km(2).

Selecting a more realistic uncertainty factor: Reducing compounding effects of multiple uncertainties

Abstract Available toxicology datasets provide a unique opportunity to validate some of the currently used Uncertainty Factors in the development of acceptable exposure levels for noncancer effects. Toxicity studies from two separate sources, the FAO/WHO database on pesticides (1978–1987) and the Monsanto database (through 1988) were chosen to evaluate three of the five currently used Uncertainty Factors. Interspecies differences in NOELs between the three mammalian species evaluated are equal to or less than a factor of 10 for both the FAO/WHO data and the Monsanto data in greater than 90% of the cases evaluated. Median values for the comparison of interspecies NOELs were 3.0 or less for all comparisons except the comparison between the mouse and rat for the Monsanto dataset where the median value was 7.5. Analyses of the Monsanto toxicity database show that the reprotoxicity NOELs were always equivalent to or higher than the chronic or subchronic NOELs for the same material. Therefore, even without conduct of a specific study to address reproductive effects, reasonable protection from adverse reproductive effects can be afforded by use of either subchronic or chronic study NOELs without application of UFD. The median ratio of subchronic NOELs and chronic NOELs was 4, and for a majority of the studies the difference between the NOELs was within one order of magnitude. Our analysis aids in validating the assumption that the upperbound for individual uncertainties maybe accounted for by use of 10‐fold uncertainty factors. However, the current U.S. Environmental Protection Agency (USEPA) reference doses/concentrations may be overly conservative because upperbounds of each of the uncertainty factors are used and each of the uncertainty factors are considered to be independent variables. Because uncertainties are probably not independent variables, the influence of compounding upperbounds when multiple uncertainty factors are used is generally only considered when four or more areas of uncertainty are outstanding. When multiple uncertainties exist, we recommend upperbound estimates only be used for the first two Uncertainty Factors, and median values be used to account for the remaining uncertainties.

Comparisons of Estimated Human Body Burdens of Dioxinlike Chemicals and TCDD Body Burdens in Experimentally Exposed Animals

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

Negative selection in hepatic tumor promotion in relation to cancer risk assessment

Mechanistic studies with phenobarbital (PB), 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) and other liver tumor promoters support a general model of promotion involving negative selection where specifically-mutated cells derive a growth advantage in the presence of persistent mitosuppression. Exposure to these liver tumor promoters appears to transiently enhance hepatocyte replication, presumably via transcriptional activation of growth regulatory genes, leading to a homeostatic increase in mitoinhibitory growth factors in the liver to constrain proliferation. Transforming growth factor beta 1 (TGF-β), a potent mitoinhibitory growth factor for hepatocytes, has been associated with the mitosuppression caused by PB and certain peroxisomal proliferators. Escape from TGF-β mitosuppression may involve loss or alteration of function of the mannose 6-phosphate/insulin-like growth factor II (M6P/IGFII) receptor, which is required for TGF-β 1 activation, or alterations of the TGF-β types I, II and III signal transduction receptors. A risk assessment based on a negative selection mechanism could be conducted for tumor promotion endpoints with TCDD and compared with current approaches that implicitly regard TCDD as an initiator. Benchmark dose calculation using centrilobular induction of cytochromes P450 1A1 and 1A2 as a surrogate for periportal growth stimulation would provide a rational starting point for application of conventional safety factor approaches, similar to those used with non-cancer effects. In the future, tissue and plasma concentrations of specific growth factors e.g. TGF-β or hepatocyte growth factor, HGF, might be considered as more direct dose surrogates for tumor-promoting effects of xenobiotics. Uncertainty factor adjustments to a TCDD benchmark dose calculation should eventually rely on direct knowledge of regulation of specific growth regulatory genes and their receptors in relevant species and on species differences in TCDD pharmacokinetics, instead of application of default animal-to-human and interindividual uncertainty factors.

Benchmark Dose Workshop: Criteria for Use of a Benchmark Dose to Estimate a Reference Dose

The purpose of the Benchmark Dose Workshop was to assess the feasibility and implications of replacing the no observed adverse effect level (NOAEL) with a benchmark dose (BRID) when deriving reference doses and concentrations (RfDs and RfCs). The workshop participants supported the use of the BMD method to remove many of the limitations inherent in using the NOAEL approach, Participants endorsed in general the use of a BMD for all quantal noncancer health effects and endorsed in particular the BMD for assessing developmental toxicity based on data presented at the workshop. The discussions of implementation recognized the need to demonstrate that changing from a NOAEL to a BMD gives the risk manager more certain information on which to base decisions, Most participants agreed that the current NOAEL-derived RfDs and RfCs are sufficiently protective and should only be changed as data become available for estimating a BMD. It was recognized that to achieve general acceptance of the BMD approach, it will have to be applied to a variety of endpoints.

Reversibility of Effects: Overview and Reproductive Systems

AbstractRecovery from adverse noncancer health effects may occur in some circumstances after cessation of exposure or after adaptation to continuing low-dose exposure. In this overview, factors that influence the reversibility of toxic effects of environmental chemicals are presented, using examples derived from toxicity to the reproductive system. Aspects that must be considered include exposure scenario, stage of the life cycle at which exposure occurs, and the nature of the toxicity. Selected categories of reproductive effects are considered briefly with respect to potential for recovery. Finally, the incorporation of reversibility into risk assessments is discussed

Risk assessment of formaldehyde

In April 1987, the Environmental Protection Agency (EPA) issued the “Assessment of Health Risks to Garment Workers and Certain Home Residents from Exposure to Formaldehyde” in which formaldehyde was classified as a carcinogen and an irritant to the eyes and respiratory tract. A quantitative risk assessment for cancer was presented. A more current document, a draft released in 1991, incorporates some additional data on the epidemiology and toxicology of formaldehyde that the EPA has received since completion of the earlier assessment, and examines the impact of this information on the estimates of health risks following exposure to airborne formaldehyde. For noncancer effects, the new data support earlier conclusions with regard to the irritant effects of formaldehyde and the dose-response gradient for these effects. The cancer assessment incorporates the use of a molecular dosimeter for the derivation of risk estimates. Tissue levels of this dosimeter, a covalent cross-link product of formaldehyde and DNA-protein (DPX), are available from rats and monkeys. The risk estimates obtained with this dosimeter are considerably lower than those obtained by conventional approaches.

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.

Wood smoke: emissions and noncancer respiratory effects.

In conclusion, this review reveals much about the constituents and fate of wood smoke but not enough about the health effects. Animal toxicological studies show that wood smoke exposure can disrupt cellular membranes, depress macrophage activity, destroy ciliated and secretory respiratory epithelial cells, and cause aberrations in biochemical enzyme levels. With respect to the human epidemiological data, the literature summarized in Table 4 shows a coherence of the data from young children, with 7/8 studies especially in children with asthma, reporting increased respiratory symptoms, lower respiratory infection, and decreased pulmonary function as a result of exposure to wood smoke. As Bates (6) has discussed, coherence of the data, although not amenable to statistical tests, carries the weight of linkage and plausibility. These adverse respiratory effects associated with wood smoke exposure also comply with many of Brandon Hill's aspects of association necessary to establish causation (40). There is strength of association, consistency (7/8 studies showing positive associations), temporality, plausibility, coherence, and analogy (using ETS exposure; 70, 94). A biological gradient has not been shown, although one is suggested in the study of pulmonary function in wildfire fighters. We conclude that the preponderance of the data suggest a causal relationship between elevated wood smoke levels and adverse respiratory health outcomes in young children.

Setting Health-Protective Soil Concentrations for Dermal Contact Allergens: A Proposed Methodology

Health-based cleanup goals for contaminated soils are typically established to protect potentially exposed individuals from increased incidences of cancer and serious noncancer effects. However, at least one regulatory agency has suggested that, for certain contact allergens such as hexavalent chromium, soil remedial goals should also consider the potential occurrence of allergic contact dermatitis (ACD) in sensitized individuals (NJDEPE, 1992). To date, appropriate risk assessment methods for setting ACD-based soil concentrations have not been addressed in the scientific literature. This paper defines and discusses the three key data needs for establishing ACD-based soil concentrations: (1) dose-response data from human patch-testing studies, in which the patch concentrations are reported in terms of mass of allergen per unit area of skin, (2) accurate estimates of the degree to which soil adheres to skin on a soil mass per unit area of skin basis, and (3) accurate estimates of the degree to which the allergen leaches from soil into human sweat. The requisite basis for each of these factors and suggested methods for obtaining and evaluating the necessary data are presented. In addition, two example calculations are presented for setting ACD-based goals for hexavalent and trivalent chromium in chromite ore-processing residues.

Future directions and research needs.

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

Future Directions and Research Needs

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

Risk Characterization Framework for Noncancer End Points

The nature of both indoor air exposures and noncancer end points present significant issues for risk characterization. Noncancer end points are multidimensional, affecting various organs, and are assumed to have thresholds. Symptoms also vary in severity within a population. In addition to the complexity of noncancer risk assessment, indoor air exposures are typified by the presence of complex mixtures, which further complicates the complex nature of noncancer risk characterization. Most noncancer risk assessment efforts have focused on defining acceptable daily intakes or reference doses (RfD) rather than estimating incidence and severity of the wide range of effects within an exposed population. The risk characterization framework has been developed to accommodate the RfD approach but, more importantly, to address the multidimensional nature of noncancer risk characterization. Newly emerging methods and standard EPA risk assessment guidelines for noncancer effects and complex mixtures were used as guides for developing the framework. Information and data needs have been identified from the framework. Peak, average, and cumulative doses from indoor air exposures are highly dependent on variable indoor air concentrations and affected by time-activity patterns. Susceptibility also plays a significant role in noncancer end points and, unlike susceptibility in cancer risk assessment, is quantifiable. This paper highlights the risk characterization framework for noncancer health risks that we developed in cooperation with the U.S. Environmental Protection Agency Environmental Criteria and Assessment Office. Additionally, a preliminary application of the framework to a complex mixture of volatile organic compounds from indoor sources is illustrated.

Risk characterization framework for noncancer end points.

The nature of both indoor air exposures and noncancer end points present significant issues for risk characterization. Noncancer end points are multidimensional, affecting various organs, and are assumed to have thresholds. Symptoms also vary in severity within a population. In addition to the complexity of noncancer risk assessment, indoor air exposures are typified by the presence of complex mixtures, which further complicates the complex nature of noncancer risk characterization. Most noncancer risk assessment efforts have focused on defining acceptable daily intakes or reference doses (RfD) rather than estimating incidence and severity of the wide range of effects within an exposed population. The risk characterization framework has been developed to accommodate the RfD approach but, more importantly, to address the multidimensional nature of noncancer risk characterization. Newly emerging methods and standard EPA risk assessment guidelines for noncancer effects and complex mixtures were used as guides for developing the framework. Information and data needs have been identified from the framework. Peak, average, and cumulative doses from indoor air exposures are highly dependent on variable indoor air concentrations and affected by time-activity patterns. Susceptibility also plays a significant role in noncancer end points and, unlike susceptibility in cancer risk assessment, is quantifiable. This paper highlights the risk characterization framework for noncancer health risks that we developed in cooperation with the U.S. Environmental Protection Agency Environmental Criteria and Assessment Office. Additionally, a preliminary application of the framework to a complex mixture of volatile organic compounds from indoor sources is illustrated.

Catalog of Risks Extended and Updated

A large variety of risks are quantified in terms of the loss of life expectancy they cause in the United States. Risks considered include the following: diseases; accidents of various types at home, at work, in public, and in motor vehicles; unemployment; poor social connections; use of small cars; smoking; air pollution; other environmental pollutants leading to cancer and non-cancer effects; purposely ingested substances; sports participation; geography; medical care; epidemics; natural hazards; socioeconomic factors; Rn and other radiation; and energy conservation. A few suggestions for applications of this catalog of risks are offered.

The U.S. and the World Economy in Transition

In the United States, 48 million adults smoke 3.5-5 x 10(11) cigarettes/year. Many cigarettes are smoked in private residences, causing regular environmental tobacco smoke (ETS) exposure to roughly 31 million nonsmokers (11% of the US population), including 16 million juveniles. (Upper bound estimates are 53 million exposed nonsmokers including 28 million juveniles.) ETS contains many chemical species whose industrial emissions are regulated by the US federal government as hazardous air pollutants (HAPs). In this paper, average daily residential exposures to and intakes of 16 HAPs in ETS are estimated for US nonsmokers who live with smokers. The evaluation is based on material-balance modeling; utilizes published data on smoking habits, demographics, and housing; and incorporates newly reported exposure-relevant emission factors. The ratio of estimated average exposure concentrations to reference concentrations is close to or greater than one for acrolein, acetaldehyde, 1,3-butadiene, and formaldehyde, indicating potential for concern regarding noncancer health effects from chronic exposures. In addition, lifetime cancer risks from residential ETS exposure are estimated to be substantial (similar to2-500 per million) for each of five known or probable human carcinogens: acetaldehyde, formaldehyde, benzene, acrylonitrile, and 1,3-butadiene. Cumulative population intakes from residential ETS are compared for six key compounds against ambient sources of exposure. ETS is found to be a dominant source of environmental inhalation intake for acrylonitrile and 1,3-butadiene. It is an important cause of intake for acetaldehyde, acrolein, and formaldehyde, and a significant contributor to intake for benzene.

Non-cancer effects of exposure to A-bomb radiation.

A slight rearrangement of the data included in a recent report from the Radiation Effects Research Foundation (RERF) has shown differences between cardiovascular and other non-malignant diseases of A-bomb survivors which probably result from two factors: selection effects of early infection deaths and residual effects of marrow damage. Both effects were dose related but neither was obvious becasue one reduced the risk of later infection deaths and the other increased the risk. Allowance for these factors is bound to alter present RERF estimates for cancer effects of radiation and the change will probably be in an upward direction, thus bringing these estimates closer to ones based on radiation workers.