Human health risk assessment: a historical overview and alternative paths forward.

Risk assessment has become a more structured activity during the past 50 years and increasingly is being used to inform major policy decisions. Much use has been made of the hazard identification phase of risk assessment to identify potentially hazardous materials or situations and guide actions to minimize potential risks. Much less frequently the process has been carried further, with estimates developed of the potency of the hazardous agent for causing adverse effects. And even less frequently, robust estimates of exposure have been developed. Thus, in only a few instances have risks been fully characterized in quantitative terms for either individuals or populations. To develop scientifically valid risk characterizations for many chemicals, much more scientific information must be acquired in a targeted manner to establish the potency of chemicals for causing cancer or other adverse health effects. Similar substantial effort must also be applied to characterizing the exposure populations receive from specific chemicals released from various source categories. In the absence of these scientifically rigorous approaches it is likely that societal actions will be guided primarily by identification of potential hazardous agents, with attempts made to minimize the hazard by banning or restricting use of the agent. This precautionary approach may not yield the maximum reduction in health risks to society for the investments made and, in addition, may deny society access to materials or processes that under appropriate conditions of use would not result in significant health risks and may indeed, have substantial net benefits to society.

Pulmonary retention and clearance of inhaled biopersistent aerosol particles: data-reducing interpolation models and models of physiologically based systems--a review of recent progress and remaining problems.

During the last 40 years, most models of long-term clearance and retention of biopersistent particles in the pulmonary region of the lung were phenomenologically oriented and accounted for only a small portion of the growing insight into lung dynamics by pulmologists, histologists, and biochemists. In this review, theoretical developments of modeling pulmonary dynamics for biopersistent particles during or after inhalation exposure are discussed. Several characteristic examples are given of the present state of the art. Most of the models presently in use are pragmatical compartmental models with a single compartment for the pulmonary region. They relate to observed data and facilitate an interpolation within the range covered by observation. Occasionally, these models are unjustifiably used for extrapolations in efforts to derive hypothetical risk assessments. Modeling efforts aiming at models of physiologically based pulmonary systems with a potential for extrapolations are not common and were published only during the last decade. Of this kind of approach, the review covers four examples. Promising progress has been made, but scarcity of supporting experimental data slows validation and extension. The two most recent model developments are based on a hypothesis by P.E. Morrow. According to Morrow, alveolar clearance is accomplished by mobile alveolar macrophages after phagocytosis of particles on the alveolar surface. The macrophage mobility, however, and thus the efficiency of the transport to the mucociliary escalator of the tracheobronchial tract will eventually decline towards total loss of mobility after the particle burden of the macrophages exceeds a critical value. The POCK model has been evaluated for a variety of chronic and subchronic rat exposure studies with noncytotoxic aerosols and gave good simulation results. The model by Tran et al. appears to be still in the developing stage of facilitating simulations for cytotoxic aerosols, but the combination of both model approaches seems to be a sound route of future efforts.

Use of mechanistic data in assessing human risks from exposure to particles.

The ultimate goal of toxicologic investigations of both natural and man-made fibrous and nonfibrous particles is to provide essential input for the assessment of potential human risks from exposure to these materials. The development of risk assessment procedures for airborne particles has evolved over the years. The earliest assessments for naturally occurring materials used direct human observations and incorporated safety factors to arrive at allowable human exposures. More recently, there has been a need to assess the potential risk associated with production and use of certain man-made materials for which human data are not available or are inadequate. For these materials, it has been necessary to assess human risks using data obtained from studies conducted in laboratory animals and with cells or tissues. During the last several decades, it has been suggested that data on the mechanisms by which particles cause disease could be used to reduce the uncertainty in estimates of human risks of particle exposures. This article provides comments on the use of mechanistic data in the risk assessment process and suggestions for increasing the successful development and use of mechanistic data in risk assessments conducted in the future.

Diesel exhaust is not a pulmonary carcinogen in CD-1 mice exposed under conditions carcinogenic to F344 rats.

Differences among laboratory animal species in the pulmonary carcinogenicity of chronic inhalation exposure to diesel exhaust have raised several important interpretive issues. Under similar heavy exposure conditions, it is clear that diesel exhaust is a pulmonary carcinogen in rats, but not in Syrian hamsters. Previous reports give conflicting views of the response of mice, which is presently considered equivocal. This report describes carcinogenicity results from a bioassay of CD-1 mice conducted in parallel with a previously reported bioassay of F344 rats (Mauderly et al. (1987) Fundam. Appl. Toxicol. 9, 208-221). Exposure to whole diesel exhaust 7 hr/day, 5 days/week for 24 months at soot concentrations of 0.35, 3.5, or 7.1 mg/m3 caused accumulations of soot in mouse lungs similar to those in lungs of rats and, like the results from rats, did not significantly affect survival or body weight. In contrast to the dose-related neoplastic response of rats, however, the exposures of mice did not increase the incidence of lung neoplasms. This finding is consistent with other data showing that mice, as well as Syrian hamsters, differ from rats in their lung neoplastic and nonneoplastic responses to heavy, chronic inhalation exposure to diesel exhaust soot and several other particles. Although rodents serve as useful indicators of potential human carcinogenic hazards, it is not yet clear which, if any, rodent species have lung neoplastic responses that are useful for quantitative predictions of human lung cancer risk from chronic inhalation of poorly soluble, respirable particles.

Reducing uncertainty in risk assessment by using specific knowledge to replace default options.

This paper has advocated the development of specific scientific information, especially information on the mechanisms of action of chemicals, to use in place of default options in assessing human cancer risks. Four examples have been discussed that build largely on information from the CIIT research program. These four examples are worthy of consideration as a group, with a view to developing insights for increasing the effectiveness and efficiency of obtaining such data in the future and, most of all, to increase their acceptance for use instead of default options. In my view, key features of all four examples are that the data are framed within an exposure-dose-response paradigm and that there is a clear linkage to the end point of concern-cancer. As the number of techniques available for making observations at the cellular and molecular levels continues to increase at a rapid pace, linking these observations to the health end points of concern such as cancer is going to be increasingly important, especially in enhancing the value of the observations for risk assessment purposes. Equally as important, the mechanistic observations must be linked to realistic exposures and associated tissue dose that can be related to realistic human exposure scenarios. In my opinion, the likelihood of obtaining information of value for risk assessment purposes using the most sophisticated of molecular and cellular techniques will be of limited value if the exposures or doses are not realistically linked to those likely to be encountered by humans. The mechanism of alpha 2u-globulin nephropathy and its association with kidney tumors in male rats and the conclusion that the male rat kidney tumor findings are not applicable to assessing human cancer risk is an example of a qualitative decision. I suspect this may be a somewhat unusual case. As one looks across the various mammalian species used for experimentation and makes comparisons with humans, a unifying theme is the relative abundance of similarities. Indeed, this is a major argument for the use of laboratory animals to obtain information relevant to humans. Nonetheless, vigilance to differences among species is important. When differences are observed, we must capitalize on them to better understand the underlying biological mechanisms that mediate the differences. If, as I have suggested, laboratory animal species are more like than different from humans in their basic biological characteristics, there is a rationale for continuing to use laboratory animals as sources of data to help assess human risks of exposure to chemicals. It follows from this that quantitative differences among species such as observed with both formaldehyde and 1,3-butadiene assume major importance for assessing human risks. In my opinion, quantitation of the likely human carcinogenic potency of chemicals is of major importance. It is not sufficient to simply classify chemicals with regard to the likelihood of their being human carcinogens, as done by IARC (1994) and U.S. EPA (1986). IARC has placed more than 60 chemicals or processes (such as coke production) in group 1, carcinogenic to humans; more than 50 in group 2a, probably carcinogenic to humans; and 250 in group 2b, possibly carcinogenic to humans. This rank order implies differing levels of concern for three categories. However, even this rough three-bin system does not convey a very clear picture as to the degree of concern that should be accorded a given chemical for producing cancer. For example, the chemicals categorized as group 1, human carcinogens, using potency estimates developed by the U.S. EPA differ in potency by roughly 4 orders of magnitude. For example, a lifetime cancer risk is 6.2 x 10(-2) per micrograms/m3 for bischloromethyl ether and 8.3 x 10(-6) for benzene (NRC, 1994). Differences such as this offer strong arguments for complementing simplistic hazard identification schemes such as the IARC and EPA carcinogen classification systems w

Risk assessment and biological mechanisms: lessons learned, future opportunities.

During the past decade, toxicological research has been dominated by two themes; investigations to elucidate the mechanisms of action of toxicants and studies to provide information to support improved assessments of human health risks. The conduct of mechanistic investigations was given an early impetus by advances in biochemistry and cell biology and, more recently, by related advances in molecular biology. Research to provide information for improved human health risk assessments was stimulated by the 1983 NAS/NRC report that provided a codified structure for conducting risk assessments. At first glance, it would appear that the two themes are closely related and, indeed, should represent parts of a joined theme. However, examination of the toxicology/risk assessment literature of the past decade indicates that this has not been the case. Reports of mechanistic studies infrequently indicate how the information can be used to provide improved estimates of human risk from exposure to toxicants. If reference is made, it is usually qualitative in nature. Neither is examination of the risk assessment literature reassuring. Mechanistic studies may be cited; however, the final step of the process, risk characterization, is usually dominated by the use of default options grounded in conservative interpretations of generic scientific knowledge. Two examples are reviewed that stand out as illustrations of how mechanistic information can be used to make a difference in risk assessments: (1) consideration of the alpha 2u-globulin-mediated mechanism for evaluating male rat data for relevance in assessing human risks of renal cancer and (2) the use of DNA-protein cross-links as an internal dose metric in cross-species extrapolation of nasal cancer risks from inhaled formaldehyde. This paper reviews past experience on these topics and suggests a strategy for increasing the use of mechanistic information in risk assessments. A key component of the strategy is to use the risk assessment process to identify research needs/opportunities that, if addressed, will reduce the use of default options, thereby reducing the uncertainties in risk assessments. Another component of the strategy is to identify a few chemicals anticipated to exert their effect via different mechanisms and whose mechanisms of dosimetry and disease pathogenesis can be investigated in-depth within a risk assessment framework; this identification will create prototype approaches as alternatives to the use of default options that have major impact on the outcome of the risk assessment process.

Assessing health risks of synthetic vitreous fibers: an integrative approach.

This paper reviews a tiered approach to acquiring information from multiple experimental systems to understand and assess the potential human health risks of exposure to airborne synthetic fibers. The approach is grounded in the now widely accepted research-risk assessment-risk management paradigm. It involves the acquisition of information that will provide mechanistic linkages within the exposure-dose-response paradigm. It advocates the use of the inhalation route of exposure for developing relevant information for assessing human health risks and calls attention to serious problems encountered using nonphysiologic routes of administration to assess human health risks.

A commentary on the NRC report "Science and judgment in risk assessment".

This article provides a brief overview of the report "Science and Judgment in Risk Assessment," prepared by a Committee of the National Research Council/National Academy of Science in response to a U.S. Environmental Protection Agency request mandated by the Clean Air Act Amendments of 1990 (CAAA-1990). The report critiques EPA's current approaches for characterizing human cancer risks from exposure to chemicals and offers recommendations for the conduct of future cancer risk assessments, especially those required in implementing the CAAA-1990 provisions which are concerned with hazardous air pollutants. The report offers specific recommendations that address the role of default options, data needs, methods and models, uncertainty, variability, and the aggregation of data. A cross-cutting theme of the report is the use of an iterative approach in which screening assessments with limited data and, of necessity, default options used in the absence of specific scientific data may be performed initially followed by subsequent assessments, as needed, in which increasing amounts of data are developed and incorporated. In some instances, the specific data on a given chemical or pollutant source will replace conservative default options used in earlier assignments. The report includes two authored appendices that address issues related to the use of default options and their replacement by specific scientific information. One appendix by Finkel advocates a principle of "plausible conservatism" for choosing and altering default options and in making cancer risk estimates. A second appendix by McClellan and North advocates the full use of scientific information in the risk assessment process. This article gives major attention to the key aspects of the NRC/NAS report, especially those dealing with the use and replacement of default options. The default options and the extent to which the options are replaced with specific science have major impact on the final quantitation of cancer risk for exposure to chemicals.

Role of biopersistence in the pathogenicity of man-made fibers and methods for evaluating biopersistence: a summary of two round-table discussions.

This paper summarizes two roundtable discussions held at the conclusion of the International Conference on Biopersistence of Respirable Synthetic Fibres and Minerals. The first round table addressed the role of biopersistence in the pathogenicity of fiber-induced disease. The panel included T. W. Hesterberg (Chairman), J.M.G. Davis, K. Donaldson, B. Fubini, N.F. Johnson, G. Oberdoerster, P. Sébastien, and D. Warheit. The second panel addressed the issue of methods for assessing biopersistence. It included R.O. McClellan (Chairman), J. Brain, A. Langer, A. Morgan, C. Morscheidt, H. Muhle, and R. Musselman. The two chairmen acknowledge the excellent contributions of all the members of the panels, whose comments formed the basis of this summary. Nonetheless, the authors assume full responsibility for the written text, recognizing that it was not reviewed by the discussants of the two panels.-Environ Health Perspect 102(Suppl 5):277-283 (1994)

Approaches to evaluating the toxicity and carcinogenicity of man-made fibers: summary of a workshop held November 11-13, 1991, Durham, North Carolina.

The Workshop on Approaches to Evaluating the Toxicity and Carcinogenicity of Man-Made Fibers (MMF) was held in Durham, North Carolina, on November 11-13, 1991. The goal of the workshop was to reach a consensus, or to determine the extent to which a consensus existed, in two areas. Participants were asked to identify scientifically sound approaches for evaluating the toxicity and carcinogenicity of man-made fibers based on today's science and to determine research appropriate for study during the next 5 years that can provide an improved scientific basis for future revisions of approaches used to evaluate man-made fiber toxicity and carcinogenicity. During the first day, a series of "state of knowledge" presentations were made to provide all participants with a common data base from which to interact and discuss scientific issues. The workshop participants were assigned to one of four discussion groups, which met separately in three half-day sessions following the first day of presentations. All groups discussed the same topics: exposure assessment, hazard identification, and dose-response information needed to integrate to characterize risk in the first session; approaches to obtaining the needed information in the second session; and recommended approaches and guidelines for evaluating the toxicity and carcinogenicity of MMF and research needs in the third session. The workshop participants reconvened as a whole after each discussion session, and one member from each group reported the group's conclusions. A closure period was also included at the end of the workshop for review and discussion of items that had been considered during the workshop. The primary conclusions reached were the following: -All fiber types capable of depositing in the thorax are not alike in their pathogenic potential. -Only fiber samples with dimensions similar to those to which humans can inhale should be tested. -A complete characterization (i.e., dimensions, fiber number, mass, and aerodynamic diameter) of the fiber aerosol and retained dose is essential. -Appropriate aerosol generation methods must be used for inhalation studies in order to preserve fiber lengths. -A tiered approach to toxicity evaluation is recommended that includes: 1. In vitro screening for durability, surface properties, cytotoxicity, and similar properties, etc; 2. Short-term inhalation or other in vivo studies; 3. That chronic inhalation studies are the "gold standard" (i.e., provide most appropriate data for risk characterization). -The rat is the most appropriate species for inhalation studies. -In chronic inhalation studies, animals should be retained to at least 20% survival after 2-year exposure. -Serial lung burden analyses are an essential component of inhalation studies and are essential for understanding exposure-dose-response relationships. -Studies oriented to understanding mechanisms of toxicity and carcinogenicity are important adjuncts to traditional toxicity studies. -Histopathological analyses of tissues of the respiratory tract represent primary endpoints for evaluating effects of inhaled fibers. Major effects include pulmonary fibrosis, lung tumors, and mesotheliomas. Experimental tissues should be archived for future studies; wherever possible, handling and preservation of tissues should be done in a way that maximizes their future use in mechanistic studies. -Potential human exposures throughout the entire life-cycle of the fiber must be considered and fibrous material for toxicologic studies prepared accordingly. -Intracavity studies are inappropriate for risk characterization but can play a useful screening role in assessing fiber toxicity.(ABSTRACT TRUNCATED AT 400 WORDS)

Distribution and biological effects of inhaled 239Pu(NO3)4 in cynomolgus monkeys.

Twenty male cynomolgus monkeys were exposed by inhalation either to an aerosol of 239Pu(NO3)4 to produce projected initial lung burdens of either 40, 10, or 4 kBq or to a carrier aerosol as a control. Animals died or were sacrificed at 0.01, 1, 3, 6, 12, 24, 40, and 99 months after inhalation, and the distribution and biological effects of the 239Pu were determined. The 239Pu cleared efficiently from the lungs so that less than 0.05 kBq remained at 99 months after exposure to 40 kBq. Total skeletal 239Pu activity was nearly constant after the first year, but the fraction of the body burden in skeleton at sacrifice increased with time up to 99 months because of clearance from other organs. Plutonium in the liver increased to a peak at 1 year and then decreased to about 10% of the peak value at 99 months. Plutonium in the testes was localized in the interstitial tissue with only 0.01 to 0.002% of the projected lung burden remaining in testes at 99 months after inhalation. Three animals exposed to 40 kBq of 239Pu died of radiation-related pulmonary pneumonitis and fibrosis. A primary papillary adenocarcinoma of the lung was identified in one animal exposed to 40 kBq initial lung burden and sacrificed 99 months after inhalation. The frequency of chromosome aberrations in blood lymphocytes was significantly elevated only in monkeys with projected deposits of 40 kBq of 239Pu. There was no change in aberration frequency in other exposure groups as a function of inhaled activity, time after exposure, or calculated total dose to the lungs. Only in monkeys that had marked radiation-induced pathological changes in the lung did the frequency of chromosome-type aberrations increase significantly, to a value about twice the control level. In cynomolgus monkeys, chromosome aberration frequency in blood lymphocytes is not a good indicator of radiation dose or damage from inhaled soluble plutonium.

Biologically based modeling in toxicology research.

Biologically based modeling can be described as the process by which the specific mechanistic steps governing tissue disposition and toxic action of chemicals are expressed in quantitative terms by a set of equations leading to prediction of the outcome of specific toxicological experiments by computer simulation. These models are useful in risk assessment because their mechanistic biological basis permits the high-to-low dose, route to route and interspecies extrapolation of the tissue disposition and toxic action of chemicals. By far their greatest utility is not as "finished" risk assessment models, but as research tools that convey a quantitative expression of our hypotheses of tissue disposition and toxic action of a chemical. A structured modeling approach to toxicology problems helps identify the data gaps in the areas of chemical disposition and toxic action, thus prioritizing on-going research to obtain critical information required to conduct quantitative risk assessment. This paper examines progress in developing comprehensive biologically based models for cancer induction by non-genotoxic carcinogens that are cytotoxic in target tissues. The strategies for linking the models on dosimetry, cytotoxicity, and carcinogenicity are described in detail. The basic concepts and approaches discussed here can be applied to many other toxic chemicals and to toxicity endpoints other than cancer.

Lung lavage therapy to lessen the biological effects of inhaled 144Ce in dogs.

To evaluate the therapeutic effects of removal of an internally deposited radionuclide on long-term biological effects, lung lavage was used to treat dogs that had inhaled 144Ce in a relatively insoluble form, in fused aluminosilicate particles. Either 10 lung lavages were performed between Days 2 and 56 after exposure or 20 lung lavages were performed between Days 2 and 84 after exposure. Approximately one-half of the 144Ce was removed by the lavages, resulting in a corresponding reduction in the total absorbed beta dose to lung. The mean survival time of the treated dogs was 1270 days compared to 370 days for untreated dogs whose initial pulmonary burdens of 144Ce were similar. Treated dogs died late from cancers of the lung or liver, whereas the untreated dogs died at much earlier times from radiation pneumonitis. Dogs treated with lung lavage but not exposed to 144Ce had a mean survival of 4770 days. We concluded that removal of 144Ce from the lung by lavage resulted in increased survival time and in a change in the biological effects from inhaled 144Ce from early-occurring inflammatory disease to late-occurring effects, principally cancer. In addition, the biological effects occurring in the treated dogs could be better predicted from the total absorbed beta dose in the lung and the dose rate after treatment rather than from the original dose rate to the lung. Therefore, we concluded that prompt treatment to remove radioactive materials could be of significant benefit to persons accidentally exposed to high levels of airborne, relatively insoluble, radioactive particles.

Establishing aerosol exposure concentrations for inhalation toxicity studies.

Criteria for the selection of aerosol concentrations to be used in inhalation studies assessing the toxicity and carcinogenicity of chemical substances were discussed by the authors in a meeting sponsored by the National Toxicology Program. Concepts in the design of aerosol inhalation studies emerged from that meeting and are being communicated through this publication. Inhalation studies assessing the toxicity and carcinogenicity of aerosols have often used maximum exposure levels on the basis of technological feasibility. Evidence has now accumulated that the amount of pulmonary burden of deposited particles impacts on particle clearance above some as yet not well-defined exposure concentration. The sequelae are such that lung clearance decreases with increased particulate burden to the point of approaching complete cessation. This paper focuses on the major determinants in establishing maximal aerosol concentrations for use in inhalation toxicity studies with special emphasis on experimental design features to assess lung retention. The subject matter of this paper is a rapidly developing area in terms of knowledge. Accordingly, the contents of this article are intended as guidelines and not as absolute rules for the conduct and interpretation of inhalation exposure studies.

Effects of adsorption of benzo[a]pyrene onto carbon black particles on levels of DNA adducts in lungs of rats exposed by inhalation.

Exposure of rodents to benzo[a]pyrene (BaP) associated with particles has previously been shown to result in increased retention of BaP and metabolites in lungs. To determine if DNA damage might be enhanced, DNA adducts were measured in lungs of F344 rats following inhalation of pure BaP aerosols or BaP absorbed on carbon black particles. Groups of rats were exposed nose only to filtered air, [14C]BaP (2 mg/m3), or [14C]BaP (2 mg/m3) adsorbed on carbon black (97 mg/m3) (BaP/CB) for 4 hr/day, 1 day/week, for 12 weeks. Groups of rats were terminated at 4, 8, 12, 16, 20, and 24 weeks after the beginning of the 12-week exposure period. Retention of total 14C in lungs was used as an indicator of total reactive metabolites. DNA isolated from lungs was analyzed for adducts using a 32P-postlabeling assay. Inhalation of BaP/CB resulted in 100-fold higher levels of 14C in lungs at the end of the 12-week exposure than did inhalation of pure BaP. The halftime for the decline in 14C levels was 34 +/- 3 weeks (mean +/- SE) for rats exposed to BaP/CB and 6 +/- 2 weeks for rats exposed to pure BaP. At the end of 12 weeks of exposure, DNA adducts in lungs of rats exposed to pure BaP ranged from 2-15 adducts per 10(9) bases (mean = 7, n = 4) and in rats exposed to pure BaP absorbed on carbon black ranged from 10-12 adducts per 10(9) bases (mean = 11, n = 4); DNA adducts in lungs of sham-exposed rats ranged from 0-2 adducts per 10(9) bases (mean = 1, n = 4). The halftimes for the decline in DNA adducts in lungs were 3 +/- 1 weeks (mean +/- SE) for the rats exposed to BaP/CB and 5 +/- 2 weeks for the rats exposed to BaP. One of the DNA adducts found following exposure to both BaP and BaP/CB was tentatively identified as the BaP diol epoxide deoxyguanosine (BPDE) adduct. Levels of both total and BPDE DNA adducts were significantly increased (p less than 0.05) in lungs of rats exposed to both BaP and BaP/CB compared to levels in lungs of sham-exposed rats. There were no significant differences in levels of DNA adducts in lungs of rats exposed to BaP or BaP/CB, although the pattern of adducts was different between the two exposure modes.(ABSTRACT TRUNCATED AT 400 WORDS)

Retention patterns for inhaled particles in the lung: comparisons between laboratory animals and humans for chronic exposures.

In the absence of adequate data exclusively from studies of inhaled particles in people, the results of inhalation studies using laboratory animals are necessary to estimate particle retention in exposed people. To make accurate projections from animal studies and the limited human data, it is necessary to consider species similarities and differences in lung retention and accumulation patterns for inhaled materials. This paper reviews species similarities and differences in pulmonary retention and clearance for inhaled particles, with emphasis on animal species most commonly used in inhalation toxicology research (rats, guinea pigs, dogs, and nonhuman primates). Simulation models for these four species and for humans were used to compare projected lung burdens which would be accumulated during chronic inhalation exposures. These simulation models project an eightfold difference among these species in the lung concentration of particles per gram of lung after a 2-y chronic inhalation exposure to the same aerosol for 8 h d-1, 5 d wk-1. The largest lung accumulation would occur in guinea pigs, the smallest in rats. To reach the same target lung concentration of particles in the lungs of both animals would therefore require about an eightfold difference in air concentration of the exposure material. These comparisons are useful for selecting appropriate laboratory animal species to study as surrogates for humans, for setting aerosol concentrations to use in inhalation studies, and for making approximations of lung burdens that would result from defined exposure scenarios.

Modeling accumulations of particles in lung during chronic inhalation exposures that lead to impaired clearance.

Chronic inhalation of insoluble particles of low toxicity that produce substantial lung burdens of particles, or inhalation of particles that are highly toxic to the lung, can impair clearance. This report describes model calculations of accumulations in lung of inhaled low-toxicity diesel exhaust soot and high-toxicity Ga2O3 particles. Lung burdens of diesel soot were measured periodically during a 24-mo exposure to inhaled diesel exhaust at soot concentrations of 0, 0.35, 3.5, and 7 mg m-3, 7 h d-1, 5 d wk-1. Lung burdens of Ga2O3 were measured for 1 y after a 4-wk exposure to 23 mg Ga2O3 m-3, 2 h d-1, 5 d wk-1. Lung burdens of Ga2O3 were measured for 1 y both studies using inhaled radiolabeled tracer particles. Simulation models fit the observed lung burdens of diesel soot in rats exposed to the 3.5- and 7-mg m-3 concentrations of soot only if it was assumed that clearance remained normal for several months, then virtually stopped. Impaired clearance from high-toxicity particles occurred early after accumulations of a low burden, but that from low-toxicity particles was evident only after months of exposure, when high burdens had accumulated in lung. The impairment in clearances of Ga2O3 particles and radiolabeled tracers was similar, but the impairment in clearance of diesel soot and radiolabeled tracers differed in magnitude. This might have been related to differences in particle size and composition between the tracers and diesel soot. Particle clearance impairment should be considered both in the design of chronic exposures of laboratory animals to inhaled particles and in extrapolating the results to people.