Repeated-dose exposure

Repeated Dose Exposure. Available studies on the effects of repeated inhalation exposure of animals to BCME (Leong et al. 1971, 1981) indicate that an exposure level of 0.1 ppm is a NOAEL for most systemic effects in rats, while 1.0 ppm leads to significant injury to lung in mice. Further studies to confirm these estimates and to determine both NOAEL and LOAEL values in each species would be useful in the protection of occupationally exposed workers. 

For the pituitary hormones, and pancreatic hormones, analytical methods are in general available with species specific reagents for the mouse, rat, dog, pig and to a limited extent for rabbit. Steroid hormones can be measured readily by an array of analytical methods. Application of gene arrays and studies on gene expression are not recommended for single-dose experiments, repeated dose exposure is required (3-7 days). 

Intermediate-Duration Exposure. No reliable information is available on the effects of repeated-dose exposure in humans. Limited information is available on the effects of repeated inhalation and oral exposures to 1,1-dichloroethane in animals. The studies reviewed indicate that 1,1-dichloroethane is possibly nephrotoxic, but this effect has only been demonstrated at high doses in one of several species tested. No other toxic effects have been attributed to 1,1-dichloroethane following repeated-dose exposures in animals. An intermediate MRL could not be derived for any routes of exposure. More information on the systemic effects of repeated-dose exposures in animals, particularly by the inhalation route since this is the most likely route of human exposure, would be useful to determine whether nephrotoxic effects observed in one study are an actual result of exposure to 1,1-dichloroethane, to determine if 1,1-dichloroethane reacts like other chlorinated aliphatics (e.g., causes neuro-and liver toxicity), and to more fully assess potential human health hazards from repeated exposure to 1,1-dichloroethane. This latter justification is particularly important since repeated exposure to low levels of 1,1-dichloroethane may be of more concern than short-term exposure to very high levels based on the current use and/or disposal of this chemical. 

The appropriateness of the in vitro system depends on the relevance of the system for the exposure in the intact organism that needs to be predicted, the stability of the system over time, and the physiologically correct balance between the formation and further metabolism of reactive intermediates. Thus, if a repeated-dose exposure for humans is to be predicted, the appropriate system would be a system that is relevant for the human biotransformation system, and take into account the time of exposure as well as the fluctuations in blood concentrations, e.g., resulting from a daily single dose [41], Examples of such studies taking this into account were carried out in the EU program Predict-IV [42, 43],... 

Repeated Dose Exposure. Numerous repeated dose studies of intermediate duration have been conducted with rats, mice and other species. These studies provide extensive information on doses and treatment schedules that are lethal and hepatotoxic but do not adequately identify thresholds for these effects, particularly in species that may be more sensitive (e.g., mink). Additional repeated dose oral studies designed to examine tissues other than the liver could provide useful information on nonhepatic systemic effects of NDMA. Oral studies conducted over periods longer than 20-30 weeks may not be necessary as sufficient evidence indicates that cancer will be the predominant effect. Repeated exposure inhalation studies could provide... 

Repeated Dose Exposure. Only one study examined the health effects of 14- and 90-day ingestion of 1,1,2-trichloroethane in drinking water of animals, and it did not include histopathological... 

In repeated-dose exposures, chemicals have a chance to accumulate in the body. The level a chemical reaches in the body depends on how large and frequent the doses are as well as on the chemical s disposition in the body, i.e., its bioavailability, volume of distribution, and rate of elimination. The blood level of a chemical at any point in time in effect reflects a steady state between the amount of chemical that enters the body and the amount that leaves. The principle of mass balance (Section 2.8) can be used to estimate body burden ... 

Based on the data from controlled human studies, the NOEL for plasma cholinesterase inhibition for a single dose of chlorpyrifos is between 0.1 and 0.5 mg/kg bw/day, and the more conservative 0.1 mg/kg bw/day (100 pg/kg bw/day) is used in this assessment as the acute NOEL for chlorpyrifos. The repeated dose NOEL in humans is 0.03 mg/kg bw/day (30 pg/kg bw/day), based on plasma cholinesterase activity, and this is the basis for the establishment of the reference dose of 0.003 mg/kg bw/day (3 pg/kg bw/day) used by the EPA in assessing dietary risk to chlorpyrifos. For the work described here, both NOELs are used as bases for assessing risks to persons who have the potential for non-dietary exposure to chlorpyrifos. For exposures that are infrequent or of short duration, the 100 pg/kg bw/day NOEL is assumed to be the more appropriate value, and the lower 30 pg/kg bw/day will be used in those situations in which exposure may be considered to be more frequent. ... 

The dangerous properties of acute toxicity, irritation, corrosivity, sensitisation, repeated-dose toxicity and CMR are evaluated in terms of their potential toxic effects to workers, consumers and man exposed indirectly via the environment, based on the use for each stage in the lifecycle of the substance from which exposure can occur. Risk assessment is also required if there are reasonable grounds for concern for potential hazardous properties, e.g., from positive in vitro mutagenicity tests or structural alerts. The risk assessment involves comparing the estimated occupational or consumer exposure levels with the exposure levels at which no adverse effects are anticipated. This may be a quantitative risk assessment, based on the ratio between the two values, or a qualitative evaluation. The principles of human health risk assessment are covered in detail by Illing (a.30) and more briefly in Chapter 7 of (73). 

ADME, intended route To determine the extent of absorption, distribution, metabolism, and excretion by the intended route of exposure following a single dose and repeated doses... 

Type IV hypersensitivity responses are elicited by T lymphocytes and are controlled by accessory cells and suppressor T cells. Macrophages are also involved in that they secrete several monokines, which results in proliferation and differentiation of T cells. Thus, there are numerous points along this intricate pathway in which drugs may modulate the final response. To achieve a Type IV response, an initial high-dose exposure or repeated lower-dose exposures are applied to the skin the antigen is carried from the skin by Langerhans cells and presented to cells in the thymus to initiate T-cell proliferation and sensitization. Once sensitized, a second challenge dose will elicit an inflammatory response. Thus, before sensitivity can be assessed, each of the models used to evaluate dermal hypersensitivity requires as a minimum ... 

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