Toxicity studies, conduct

Developmental Effects. Evidence from human studies on congenital anomalies as an end point (Emhart et al. 1985, 1986 McMichael et al. 1986 Needleman et al. 1984) indicate no association between prenatal exposure to low levels of lead and the occurrence of major congenital anomalies. This conclusion is further supported by developmental toxicity studies conducted in rats and mice these studies provide no evidence that lead compounds (acetate or nitrate) are teratogenic when exposure is by natural routes (i.e., inhalation, oral, dermal). Intravenous or intraperitoneal injection of lead compounds (acetate, chloride, or nitrate) into pregnant rats, mice, or hamsters, however, has produced malformations in several studies reviewed by EPA (1986a). 

The information required to evaluate specific target organ/systemic toxicity comes either fi om single exposure in humans, e.g. exposure at home, in the workplace or environmentally, or from studies conducted in experimental animals. The standard animal studies in rats or mice that provide this information are acute toxicity studies which can include clinical observations and detailed macroscopic and microscopic examination to enable the toxic effects on target tissues/organs to be identified. Results of acute toxicity studies conducted in other species may also provide relevant information. 

The guidance values proposed refer basically to effects seen in a standard 90-day toxicity study conducted in rats. They can be used as a basis to extrapolate equivalent guidance values for toxicity studies of greater or lesser duration, using dose/exposure time extrapolation similar to Haber s rule for inhalation, which states essentially that the effective dose is directly proportional to the exposure concentration and the duration of exposure. The assessment should be done on a case-by-case basis e.g. for a 28-day study the guidance values below would be increased by a factor of three. 

The development of neutralizing antibodies against a human protein that would be foreign to the test species is a major concern. The presence or absence of a neutralizing antibody must be determined in each test species used. This could very well limit the species that are appropriate to use in safety studies, and it could limit the duration of any toxicity studies conducted. Generally, neutralizing antibody titers could develop as early as 10 to 14 days after initiation of treatment. Therefore, for a product inducing such antibodies, toxicity studies of more than approximately 14-16 days duration would not be appropriate. 

Acute and subacute toxicity studies conducted in Charles Foster rats showed that MIC exposure significantly inhibits weight gain in a dose-dependent manner. These rats showed pathological lesions in the viscera, bronchial tree, lungs, liver, and kidneys. In another study, F344 rats exposed to 3 ppm MIC for 6 h day for 4 days showed significant mortality within 28 days. 

Only circumstantial evidence is available that supports the supposition that wildlife species are exposed to explosive compounds. Studies conducted at U.S. Army ammunition plants and other areas of known soil contamination have failed to detect body burdens of suspected explosive compounds in mice, deer, and some bird species [4-7] (see Chapter 10 in this book for a more complete review). Given the relatively rapid metabolic potential of many explosives in vivo, the heterogeneous distribution of these substances in the environment, and the potential for bioaccumulation of some nitramines in plants, body burden analysis may not adequately describe exposure potential. Therefore, the data reviewed in this chapter will focus on controlled laboratory toxicity studies conducted to evaluate the effects in wildlife species, many of which were designed for specific risk assessment applications. 

All toxicity data closely resembled those obtained with the first-generation product. No adverse effects were observed in acute-and repeat-dose toxicity studies conducted in rats and rabbits, suggesting a similar toxicology profile and predicting comparable levels of safety and tolerability in humans. 

This chapter discusses issues relevant to assessing exposure of military personnel to jet-propulsion fuel 8 (JP-8). The chapter begins with a description of various scenarios under which military personnel are exposed to JP-8, followed by a brief discussion of the challenges of quantifying human exposure to this distillate fuel. The next section contains a summary of data from studies that have measured concentrations of several components of JP-8 in ambient air at Air Force aircraft maintenance sites. Studies measuring body burden of several JP-8 components in workers involved in aircraft maintenance are also presented. The final section of this chapter describes how the physical and chemical properties of JP-8 affect uptake into the body from exposure by the inhalation, dermal, and oral routes. This last section also serves as a prelude to interpretation of animal toxicity studies conducted with distillate fuels (e.g., JP-8) that are described in later chapters. 

Subchronic toxicity studies, conducted in at least two animal species, usually consist of daily administration of the drug for up to 90 days. Physical examinations and laboratoiy tests are performed throughout the study and at the end of the study to see what organs may have been adversely affected by the drug. 

A subchronic toxicity study conducted on male rhesus monkeys and male albino rats exposed over a period of 6 months (6 hours/day, 5 days/week) indicated marginal toxicity of cyanogen at 25 ppm (Lewis et al. 1984). Total lung moisture content and body weights were significantly lower. The odor threshold level for cyanogen is about 250 ppm. 

Summary of Whole-Animal Toxicity Studies Conducted Using Either Purified Domoic Acid or Extracts from Domoate-Contaminated Shellfish... 

This 4-day toxicity study conducted in juvenile fat-head minnows by the USEPA, encompassed a large series of stable, unreactive and non-ionizable compounds such as hydrocarbons, alcohols, esters, ketones and herbicides whose partition coefficients ranged from -1.30 to 6. 

Agent HD (Sulfur Mustard). RfDe = 7 x 10 mg kg d. A LOiAEL was identified in a two-generation reproductive toxicity study conducted in rats. A total uncertainty factor of 3000 was applied to account for protection of sensitive subpopulations (10), animal-to-human extrapolation (10), LOAEL-to-NOAEL extrapolation (3), and extrapolation from a subchronic to chronic exposure (10). A LOAEL-to-NOAEL UF of 3, instead of the default value of 10, was used because the critical effect (stomach lesions) was considered to be mild in severity and may have been enhanced by the vehicle used (sesame oil in which sulfur mustard is fully soluble) and the route of administration (gavage), which is more likely to result in localized irritant effects. The key study did identify a toxic effect that is consistent with the vesicant properties of sulfur mustard. In none of the other available studies was there any indication of a different effect occurring at a lower exposure level. 

The legislated or suggested concentration limits in the environment and those relating to human health are given in Tables 34.1 and 34.2. The results of aquatic and environmental toxicity studies conducted on MTBE are summarized in Table 34.3. 

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