Inhalation-animal

Renal Effects. The characteristics of early or acute lead-induced nephropathy in humans include nuclear inclusion bodies, mitochondrial changes, and cytomegaly of the proximal tubular epithelial cells dysfunction of the proximal tubules (Fanconi s syndrome) manifested as aminoaciduria, glucosuria, and phosphaturia with hypophosphatemia and increased sodium and decreased uric acid excretion. These effects appear to be reversible. Characteristics of chronic lead nephropathy include progressive interstitial fibrosis, dilation of tubules and atrophy or hyperplasia of the tubular epithelial cells, and few or no nuclear inclusion bodies, reduction in glomerular filtration rate, and azotemia. These effects are irreversible. The acute form is reported in lead-intoxicated children, whose primary exposure is via the oral route, and sometimes in lead workers. The chronic form is reported mainly in lead workers, whose primary exposure is via inhalation. Animal studies provide evidence of nephropathy similar to that which occurs in humans, particularly the acute form (see Section 2.2.3.2). 

U.S. EPA (1991) derived a cancer inhalation unit risk for sulfur mustard based on the results of inhalation animal studies conducted by McNamara et al. (1975, see Section 3.7.2) however, it was emphasized in the EPA report that the studies of McNamara et al. (1975) contained deficiencies which made a quantitative analysis difficult. Conducted in 1970, the studies do not conform to the modem norms of acceptable experimental protocol, and it is likely that there was bias in the assignment of the animals to the test categories (U.S. EPA, 1991). In addition, many of the exposures were very brief, included only a few animals, and many of the animals were sacrificed (and some were replaced) before their capacity to develop late-appearing tumors was fully developed (U.S. EPA, 1991). Despite these shortcomings, it was noted by EPA that the McNamara et al. data are the best available for estimating the carcinogenic potency of sulfur mustard. The authors of the EPA report analyzed two sets of McNamara s data one from a toxicity study and one from a carcinogenicity study (see Section 3.7.2). 

When experimental lethality data have been insufficient to determine statistically an LCqi value, but an LC50 value was determined and all exposure levels caused lethality, a fraction of the LC50 value is used to estimate the threshold for lethality. In aU cases, the exposure-response curve was steep, and the LC50 value was divided by 3. Eowles et al. (1999) analyzed 120 published inhalation animal lethality data sets using the BMC method. Their analyses of inhalation toxicity experiments revealed that for many chemicals the ratio between the LC50 and the experimentally observed nonlethal level... 

SAFETY PROFILE Poison by ingestion and intraperitoneal routes. Mildly toxic by inhalation. Animal experiments show that the vapor is a poison which causes... 

Most studies of respiratory diseases reported for uranium involve noncancerous alveolar epithelium damage in type II cells. These changes are characterized by interstitial inflammahon of the alveolar epithelium leading eventually to emphysema or pulmonary fibrosis in acute exposures or to hyperplasia, hypertrophy, and transdifferentiation (metaplasia) in chronic exposures (Cooper et al. 1982 Dungworth 1989 Stokinger 1981 Wedeen 1992). However, the lack of significant pulmonary injury in most inhalation animal studies indicates that other potentially toxic contaminants such as inhalable dust particles, radium, or radon may contribute to these effects. 

TABLE 3-2. Levels of Significant Exposure to Asbestos - inhalation - Animal Studies... 

Although the authors propose that vapor pressure can be used to predict whether a drug of abuse may be smoked, other physiochemical parameters, including particle size (Snyder et al. 1988) and lipid solubility (McQuay et al. 1989), also influence drug potency. The determination of these physiochemical parameters used concurrently with a reliable inhalation animal model will serve as useful tools for identifying which drugs may potentially be abused by inhalation. 

Intermediate Inhalation Animal Studies. Results from intermediate-duration inhalation studies with rats (Appelman et al. 1988 Feron et al. 1988 Monticello et al. 1991 Rusch et al. 1983 Woutersen et al. 1987 Zwart et al. 1988), Rhesus monkeys (Monticello et al. 1989), Cynomolgus monkeys (Rusch et al. 

Animal Cancer Studies As discussed previously in Section 2.2.1.2 subsection entitled Chronic Inhalation Animal Studies, chronic exposure to airborne formaldehyde concentrations ranging from about 6 ppm to 15 ppm induced increased incidences of nasal tumors (squamous cell carcinomas, squamous cell papillomas, or polyploid adenomas) in three bioassays with Fisher 344 rats (Kamata et al. 1997 Kems et al. 1983b Monticello et al. 1996 Swenberg et al. 1980). Increased incidences of lower respiratory tract tumors or distant site tumors were not found in these studies, and exposure to concentrations of 2 ppm and lower induced no malignant nasal tumors. 

Respiratory Effects. Three of 6 rabbits died from bronchopneumonia death of 7 of 18 guinea pigs was attributed to pneumonia and pulmonary congestion (Sunderman 1944). Results of this study are preliminary and/or inconclusive since no other inhalation animal studies have been performed. 

The Subcommittee on Permissible Exposure Levels for Military Fuels also discussed animal studies of chronic inhalation exposures to JP-4 and unleaded-gasoline vapor studies of subchronic inhalation exposures to JP-8, JP-5, and JP-4 and studies of dermal exposure (skin painting) to JP-5 and DFM (NRC 1996). No lifetime inhalation animal bioassays of JP-5, JP-8, or DFM were located. Among the studies discussed in the 1996 report, the subchronic inhalation studies ofJP-8 (Mattie etal. 1991) and the studies ofJP-5 (Gaworski et al. 1984, 1985 NTP 1986) and JP-4 (Bruner et al. 1993) are the most relevant to the present assessment. Those studies are discussed below with additional studies included in the current assessment. 

The first pathway has been studied primarily with model particles such as carbon, gold, and manganese oxide in experimental inhalation animal models and the second pathway has been evaluated through extensive research and particle surface manipulation in drug delivery, as an approach to try to get dmgs to the brain (Agarwal et al., 2009 Juillerat-Jeanneret, 2008 Borm et al., 2006 Aschner et al., 2007 Kreuter, 2004 Silva,... 

Although human toxicity to MIC has only been observed following inhalation, animal experiments reveal that it is also toxic following injection this contradicts the prediction by the visiting American team soon after the disaster that MIC is so reactive that it will be destroyed upon contact with the body. Metabolites of MIC are also toxic (Varma and Guest, 1993). 

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