Exposure, chemical subchronic

In additional EPA studies, subchronic inhalation was evaluated ia the rat for 4 and 13 weeks, respectively, and no adverse effects other than nasal irritation were noted. In the above-mentioned NTP chronic toxicity study ia mice, no chronic toxic effects other than those resulting from bronchial irritation were noted. There was no treatment-related increase ia tumors ia male mice, but female mice had a slight increase in bronchial tumors. Neither species had an increase in cancer. Naphthalene showed no biological activity in other chemical carcinogen tests, indicating Htde cancer risk (44). No incidents of chronic effects have been reported as a result of industrial exposure to naphthalene (28,41). 

Acceptable Intake for Subchronic Exposure (AIS) An estimate similar in concept to the subchronic RfD. but derived using a less strictly defined methodology. Subchronic RfDs have replaced AISs as the Agency s preferred alues for use in e ahiating potential noncarcinogenic health effects resulting from subchronic exposure to a chemical. 

Hanlon, D.P. and V.H. Ferm. 1986b. Concentration and chemical status of arsenic in the blood of pregnant hamsters during critical embryogenesis. 1. Subchronic exposure to arsenate using constant rate administration. Environ. Res. 40 372-379. 

A commonly used scheme for categorizing toxicity is based on exposure duration. Toxicologists generally seek to understand the effects of acute, chronic, and subchronic exposures. They attempt to learn for each of these three exposure categories the types of adverse effects a chemical produces, the minimum dose at which these effects are observable, and something about how these adverse effects change as the dose is increased. 

Identifying the LD50 is not the only purpose of the acute toxicity study. The LD50 provides a reasonably reliable indication of the relative acute toxicities of chemicals, and this is obviously important. But an even more important reason exists for conducting such tests, and that is to prepare the way for more extensive study of subchronic and chronic exposure. 

The toxicologist usually moves from studies of a single exposure to ones in which animals are exposed on each of 90 consecutive days. The 90-day subchronic study has become a convention in the field. Rodents usually live 2-3 years in the laboratory, so 90 days is about 10% of a lifetime. An enormous amount of 90-day rodent toxicity data have been collected over the past several decades and have played key roles in judging the risks of environmental chemicals. 

A second category of respiratory toxicity is that characterized by damage to the cells anywhere along the respiratory tract. Such damage can cause the release of fluid to the open spaces of the tract, and result in accumulation of that fluid, or edema, in several areas. These edematous reactions can occur after acute exposure to some chemicals, although the production of edema can be delayed, and arise after subchronic and chronic exposures. 

Some occupational situations, if inadequately controlled, can create opportunities for damage to the respiratory system. Exposure to certain forms of the metals nickel and cadmium, ordinarily as airborne particulates, can cause cellular damage, edema, and, if sustained for sufficiently long periods, emphysema. Many other metals, usually only in some of their many chemical forms, can produce emphysema upon subchronic or chronic exposure. 

If the NOAEL is from a study of less-than-lifetime duration and it is to be used to estimate a Dt for lifetime exposure, the NOAEL is divided by what is called an uncertainty factor (UE) of 10, because it is reasonably clear that toxic effects become apparent at lower dose as the duration of dosing increases. A UE of 10 is usually regarded as sufficient for converting a NOAEL based on exposure over a fraction of a lifetime to estimate a lifetime NOAEL. The factor of 10 is supported by some empirical evidence from observations on chemicals for which both subchronic and chronic data are available (the chronic NOAEL is rarely less than one-tenth of the subchronic NOAEL). 

Lock S, Dalbey W, Schmoyer R, et al. 1984. Chemical characterization and toxicologic evaluation of airborne mixtures Inhalation toxicology of diesel fuel obscurant aerosol in Sprague-Dawley rats. Final report, phase 3 Subchronic exposures. Oak Ridge, TN Oak Ridge National Laboratory. ORNL/TM-... 

In the test guidelines for 90-day toxicity studies (OPPTS 870.3100, 870.3150, 870.3250, 870.3465), the following definition in relation to the term subchronic is provided Subchronic... toxicity is the adverse effects occurring as a result of the repeated daily exposure of experimental animals to a chemical by the... route for a part (approximately 10 percent) of the test animal s life span. ... 

In conclusion, the traditional assessment factors (interspecies, intraspecies, subchronic-to-chronic, LOAEL-to-NOAEL, and database-deficiency) are considered to cover the concerns and uncertainties for children adequately, i.e., no children-specific assessment factor is needed when setting tolerable intakes. However, it is recommended to perform children-specific risk assessments for chemical substances in products and foods intended for children, based on specific exposure assessments for children. 

Dourson and Stara (1983) evaluated ratios of subchronic to chronic exposure for either NOAELs (30 ratios), LOAELs (22 ratios), or their combination (52 ratios) derived from the toxicity studies compiled by Weil and McCoUister (1963), see above. For more than half of the observed chemicals, ratios were 2 or less, and approximately 96% of the ratios were below a value of 10. According to the authors, this supports a 10-fold UF to account for estimating an ADI from a subchronic effect level for a chemical if a chronic level is unavailable. 

Woutersen et al. (1985, as cited in Kalberlah and Schneider 1998 ECETOC 1995, 2003) evaluated toxicity data relating to 82 substances including stabilizers, plasticizers, antioxidants, disinfectants, food additives, pesticides, other agrochemicals, and industrial chemicals. The substances were each tested (oral administration to rats) for a subacute (2-4 weeks) and a subchronic (13-18 weeks) duration of exposure. Both the NOAEL and the LOAEL were included in the comparison. For 56% of the substances (46), the ratio NOAELsubacute/ NOAELsubchronic was about 1. For 44% of the substances (36), the subchronic NOAEL was lower than the subacute NOAEL (i.e., the ratio was above 1), and for 3/82 substances, the ratio was above 100. The 95th percentile was about 10. A factor of 4 covered 70%-80% of the substances. 

The Research and Advisory Institute for Hazardous Substances (FoBiG 1996b, internal working paper as cited in Kalberlah and Schneider 1998) also performed an evaluation based on toxicological data on 10 agrochemicals and a further 3 chemicals (anonymous), by 2 manufacturers. In most cases, the LOAEL and the NOAEL for short-term (28 days), subchronic (90 days), and chronic (12-24 months) were reported. In most of the cases, it appeared immaterial whether LOAEL-to-LOAEL or NOAEL-to-NOAEL ratios for the various exposure durations were compared and consequently, overall ratios N(L)OAEL/N(L)OAEL for the various exposure durations were calculated and the ratio distributions were examined, see Table 5.6. 

Dourson and Stara (1983) made a plot of frequency versus ratios of LOAEL to NOAEL for either subchronic (27 comparisons) or chronic exposure (25 comparisons), or their combination (52 comparisons) based on data adapted from Weil and McCollister, see Section 5.6. They stated that these experimentally determined ratios can be thought of as reductions in a LOAEL found after subchronic or chronic exposure in order to yield the corresponding NOAEL. For example, a ratio of 3 indicates that the NOAEL is threefold less than the corresponding LOAEL for a particular chemical. All chemicals had ratios of 10 or less and of these ratios, 96% had values of 5 or less. The authors concluded that this analysis supported a UF between 1 and 10 to account for estimating an ADI from a LOAEL if a NOAEL is not available. 

A default assessment factor of 10 has been used traditionally for the extrapolation from a LOAEL to a NOAEL. Some analyses have been performed in order to evaluate the size of an appropriate assessment factor for the LOAEL-to-NOAEL extrapolation, based on evaluations of LOAEL/NOAEL ratios. A number of evaluations have been based on data from Weil and McCollister (1963) and adapted by Dourson and Stara (1983). Some evaluations found that this analysis supports that a factor of 10 or lower is adequate while others found the factor of 10 to be overly conservative as the LOAEL rarely exceeded the NOAEL by more than about 5-6 fold and was typically closer to a value of 3. The analysis on LOAEL/NOAEL ratios performed on LOAEL/NOAEL ratios showed 95th percentiles of 9, 16, and 11 for subacute, subchronic, and chronic exposure durations, respectively, supporting the 10-fold factor to account for about 95% of the chemicals evaluated. 

Exposure of the general population to chemicals present in the environment is an example of long-term exposure on a local or regional spatial scale. The general population is mainly exposed to environmental chemicals via oral exposure through food and drinking water and via inhalation from ambient and indoor air. The total body burden can, e.g., be expressed as a total oral intake (the outcome of the exposure assessment). This intake should be compared with a POD derived from preferably long-term studies or at least subchronic studies (outcome of the hazard (effects) assessment). 

Consumers and workers may be exposed to a variety of chemicals via different exposure routes. This exposure can be judged to be acute, subchronic, or chronic by analogy with the exposure schedules in the various experimental animal studies. The spatial scale of exposure is at the personal level. At the risk characterization step, the actual or estimated acute, subchronic, and chronic exposure level can be compared with a suitable DNEL derived from the acute, subchronic, and chronic studies, respectively. 

The SCLPs are defined as unbranched, aliphatic chains containing between nine and 18 carbon atoms, with up to three double bonds in the carbon backbone, and ending in an alcohol, aldehyde, or acetate functional group (Figure 12.5) [42]. Laboratory studies have demonstrated that there is no acute, subchronic, chronic, or developmental mammalian toxicity even with exposure to high doses of SCLPs or chemically similar compounds [39, 43]. 

A subchronic (90 d) bioassay in a mammalian species by oral exposure is the recommended minimum data for estimating an RfD. The study must meet EPA s minimum standards of quality. Ideally, the study should identify a NOAEL and a LOAEL. In the absence of these minimum data, EPA assigns the chemical to a not verifiable group, and EPA then seeks or waits for additional data before estimating RfD for that chemical. 

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