Animal inhalation studies risk assessment data

Many laboratory animal models have been used to describe the toxicity and pharmacology of chloroform. By far, the most commonly used laboratory animal species are the rat and mouse models. Generally, the pharmacokinetic and toxicokinetic data gathered from rats and mice compare favorably with the limited information available from human studies. PBPK models have been developed using pharmacokinetic and toxicokinetic data for use in risk assessment work for the human. The models are discussed in depth in Section 2.3.5. As mentioned previously, male mice have a sex-related tendency to develop severe renal disease when exposed to chloroform, particularly by the inhalation and oral exposure routes. This effect appears to be species-related as well, since experiments in rabbits and guinea pigs found no sex-related differences in renal toxicity. 

Immunotoxicity. There are currently no data on the effects of 2-hexanone on the human immune system via any route of exposure. Animal data included an inhalation study in which there was a 40% decrease in peripheral white blood cells in rats exposed to 2-hexanone (Katz et al. 1980). In addition, 2,5-hexanedione, a metabolite of 2-hexanone, was shown to adversely affect lymphoid organs of the immune system in rats and to cause impairment of immunity in mice (Upreti and Shanker 1987). Immunological assessments, including analysis of peripheral blood components and effects on lymphoid tissue, conducted as part of intermediate-or chronic-duration studies and skin sensitization tests would be useful in developing a dose-response relationship and assessing the potential risk to chronically exposed persons in the vicinity of hazardous waste sites or to exposed workers. 

Chronic-Duration Exposure and Cancer. Limited studies are available on the effects in humans chronically exposed to chlorobenzene via inhalation and suggest that nervous system is a target tissue. Specific exposure data were not provided. No information is available on effects of chlorobenzene in humans following chronic oral or dermal exposure. Inhalation and oral studies in animals identified the same target tissues as for intermediate-duration exposure. One study in rats demonstrated that the immune system can also be adversely affected via oral exposure. Inhalation studies in humans and inhalation and oral studies in animals are sufficient to identify main target tissues. A chronic MRL was not derived since human exposure data were lacking and the one animal study did not evaluate a sufficient number of end points and test animals. Further studies via the dermal route would provide additional toxicity data for an assessment of potential risk to humans. 

Additional data are needed to better define the exposure of humans and, in the context of animal toxicity studies, of laboratory animals. Because JP-8 is a complex mixture of chemicals that differ in volatility, solubility, metabolic rate and pathway, and rate and route of elimination from the body, dosimetry of critical components of the mixture at critical sites in the body is important to enhance the quality of risk assessment. The fact that human exposures can involve liquid fuel, aerosolized fuel, and vapor, by inhalation, dermal, and oral routes of exposure makes it difficult to accurately predict the internal dose of JP-8 and its components. 

The existing methods available for scientifically defensible risk characterization are not yet ideal since each step has an associated uncertainty resulting from data limitation and incomplete knowledge on exact mechanism of action of the toxic chemical on the human body. For noncancer end points, safety factors or uncertainty factors are applied since these effects are assumed to have a threshold below which no adverse effect is expected to be observed. US EPA has used the concept of a reference concentration (RfC) to estimate acceptable daily human exposure from HAPs. The RfC was adapted for inhalation studies based on a reference dose (RfD) method previously used for oral exposure assessment. The derivation of the RfC differs from that for the RfD in the use of dosimetric adjustment to extrapolate the exposure concentration for animals to a human equivalent concentration. Both are estimates, with uncertainty spaiming perhaps an order of magnitude, of a daily exposure to the human population, including sensitive subgroups, which would be without appreciable risk of deleterious effects over a lifetime. 

Reproductive Effects. No studies of reproductive effects in humans were located. In animals, hexachloroethane adversely affected fertility following oral exposure, but no effects were reported following inhalation exposure (Weeks et al. 1979). The absence of quantitative data on reproductive parameters, as well as evaluation of parameters that are pertinent to the assessment of reproductive risk, precludes any meaningful determination of the potential for hexachloroethane to cause adverse effects on human reproduction. 

Reproductive Toxicity. No studies were located regarding the reproductive effects of thorium in humans following exposure by any route. Neither inhalation nor oral reproduction studies in animals were located. Pharmacokinetic data following inhalation or oral exposure were not located to allow the prediction of possible reproductive effects. One dermal rat study found testicular effects after administration directly onto the scrotal skin. Additional inhalation, oral, and dermal reproduction studies and multigenerational studies would be helpful in assessing the potential risk to humans. 

Figure 11.6 illustrates a process to follow to assess a substance s absorption potential. The first step is to establish the types of individuals (i.e., workers, consumers, or general population) at greatest risk of exposure and the known or likely routes (dermal, inhalation, or oral) by which exposure will take place. The second step is to determine whether measured absorption data for the substance are available. Such data are often not available, but animal absorption data can be used as surrogates for human data in many cases. If no measured absorption data are available, toxicity data from studies involving humans or animals exposed to the substance may be useful. For example, if systemic toxic effects were noted in humans or animals following dermal (or oral or inhalation) exposure to a substance, especially at low doses, then obviously the substance is absorbed via this route. 

Once an assessment has determined that the data indicate human risk potential for reproductive and developmental toxicity, the next step is to perform a quantitative evaluation. Dose-response data from human and experimental animal reproductive and developmental toxicity studies are reviewed to identify a no-observed-adverse-effect level (NOAEL) or a lowest-observed-adverse-effect level (LOAEL), and/or to derive a benchmark dose (BMD). Duration adjustments of the NOAEL, LOAEL, or BMD are often made, particularly for inhalation exposures when extrapolating to different exposure scenarios. Such adjustments have not been routinely applied to developmental toxicity data. The subcommittee recommends that duration adjustments be considered for both reproductive and developmental toxicity... 

Many examples of the use of animal exposures to study the respiratory tract toxicity of inhaled chemicals are discussed in portions of this entry describing indicators of respiratory tract response. Examples cited here demonstrate ways in which animal studies are used to help protect human populations and guide assessment of human risk. For most chemicals that pose a potential inhalation risk to workers, there are insufficient human data to set safe occupational exposure limits. Using inorganic nickel compounds as an example, epidemiological data indicate an... 

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