The Setting of Particulate Exposure Levels for Chronic Inhalation Toxicity Studies

Frau n hofer-l nstitut fur Toxi kologie u nd Aerosolforschung, Hannover, Federal Republic of Germany I A subchronic inhalation study of a special test toner was conducted by exposure of groups of F-344 SPF (specific pathogen free) rats for 6 hlday, 5 dayslwk for 73 wk. The test material was a special 9OOO type xerographic toner, enriched in respirable size particles compared to commercial toner, such that it was about 35% respirable according to the ACGIH criteria. The nominal aerosol exposure concentrations were 0, 7.0, 4.0, 76.0, and 64.0 mglm? Body weight, clinical chemistry values, food consumption, and organ weights were normal except for a 40% increase in lung weight for the highest exposure group. Histopathological examination of the lungs indicated an exposure-related accumulation of particle-laden alveolar macrophages. A very slight degree of septa1 thickening of the alveolar structure was noted in the highest exposure group. Clearance results for the test material and a superimposed spike of 59Fe203 were essentially unchanged at exposure concentrations of 0, 1, and 4 mg/m3. , At 76 mg/m3, some indications of retarded clearance were noted and at 64 mg/m3, no appreciable toner clearance was observed. The pulmonary changes observed at the two highest exposure levels are interpreted on the basis of the "lung overloading" concept. Based upon the above observations, as well as the increase in lung weight, both the maximum tolerated dose (MTD) and the maximum functionally tolerated dose of test toner (MFTD) in this subchronic study were exceeded at the 64 mg/m3 exposure level.Inhalation Toxicology Downloaded from informahealthcare.com by University of Auckland on 11/18/14For personal use only.

“…A broad discussion of this topic has been provided by Morrow (1986). The concept of the maximum tolerated dose (MTD) has been widely used in long-term bioassays.…”

Section: Discussionmentioning

confidence: 99%

Subchronic Inhalation Study of Toner in Rats

Muhle

Bellmann

Creutzenberg

et al. 1990

“…Expressed in terms of mass, overload has been reported to occur when burdens of a dust exceed 1 mg/g lung (Morrow, 1986). It has also been reported that volume, not mass, of phagocytized particles determines the extent of overloading (Morrow, 1988).…”

Section: Experimental Dust Overload (Intraluminal Dust Loading)mentioning

confidence: 97%

Comparative Pathology of Dust-Induced Pulmonary Lesions: Significance of Animal Studies to Humans

Schultz

1996

The proper interpretation of animal experiments on particulate materials i s essential in order to properly identify the relative risk associated with human exposure to these materials. This article reviews the pathology of experimental dust-induced pulmonary lesions, discusses factors necessary for the proper interpretation of these results, and makes recommendations for the design and conduct of future studies. In experimental studies, animals are often exposed to high concentrations of dusts that overwhelm normal lung clearance mechanisms, resulting in the somewhat poorly defined condition of "dust overload." The pulmonary response to this intra-alveolar dust loading is nonspecific and thus morphologically similar regardless of the dust type studied. In the rat, these lesions are characterized by alveolar macrophage accumulation, necrosis of pneumocytes, granuloma formation, fibrosis, and bronchiolarization and squamous metaplasia of alveoli. Depending on exposurz concentration and duration, bronchiolealveolar ademonas and adenocarcinomas and cystic keratinizing squamous lesions may occur. The squamous lesions appear to represent a response unique to the rat. The significance of studies using dust concentrations that produce these nonspecific lesions is questionable since such conditions, with extreme exception, do not occur in humans. Further, fibrogenic or carcinogenic properties that may be specific to a particular dust at exposure concentrations relevant to humans may actually be masked by the nonspecific response that occurs following dust overload. Studies with dust at concentrations that produce an interstitial dust loading but that are below the threshold for intra-alveolar dust overload are more relevant for human health hazard identification. This has been best demonstrated by the results of numerous studies with asbestos in rats where fibrosis and neoplasia, morphologically similar to that seen in humans, have been produced in the absence of the nonspecific lesions seen in dust overload. The interpretation of studies where dusts are administrated by nonconventional routes should also be undertaken with caution. for example, serosa tests bypass an important mechanistic step in fiber-induced mesothelioma, namely, the ability of a dust to reach the pleura surface following inhalation. In addition, such tests may produce diagnostic dilemmas since reactive changes on serosal surfaces, which are expected following application of any foreign substance, may be difficult to differentiate from a neoplastic response. Future studies to assess the human health hazards of fibrous and nonfibrous dusts should be conducted at concentrations that allow for the characterization of responses specific to a given dust and by exposure routes most representative of that experienced by humans.

“…Morrow (1986aMorrow ( , 1986b noted that the classic MTD is inappropriate for inhalation studies of poorly soluble particles of low intrinsic toxicity, primarily because, unlike liquids or vapors, particles are retained within the target organ (lungs) and can overwhelm macrophage-mediated clearance, resulting in injury that is nonspecific to the particle composition. Pulmonary injury is indicated by accumulation of macrophages and other inflammatory cells, cell proliferation in lung epithelium, and the presence of dust in the interstitium and lymphatics.…”

Section: Criteria For Establishing the Mtd In Fiber Inhalation Studiesmentioning

confidence: 99%

Studies on the Inhalation Toxicology of Two Fiberglasses and Amosite Asbestos in the Syrian Golden Hamster. Part I. Results of a Subchronic Study and Dose Selection for a Chronic Study

Hesterberg¹,

Axten²,

McConnell

et al. 1999

A multidose, subchronic inhalation study was used to estimate the maximum tolerated dose (MTD) of 901 fiberglass (MMVF10.1) for a chronic inhalation study using hamsters. Subchronic study results indicated that 30 mg/m(3) [250-300 WHO fibers (>5 microm long)/cm(3) and 100-130 fibers/cm(3) >20 microm long] meets or exceeds the estimated MTD, and chronic study results confirmed this. For the subchronic study, hamsters were exposed 6 h/day, 5 days/wk, for 13 wk to MMVF10.1 at 3, 16, 30, 45, and 60 mg/m(3) (36, 206, 316, 552, or 714 WHO fibers/cm(3)), then monitored for 10 wk. Results demonstrating MTD were: inflammatory response (all fiber exposures); elevated lung cell proliferation with @ges;16 mg/m(3); lung lavage neutrophil elevations with @ges;16 mg/m(3) and lactate dehydrogenase (LDH) and protein elevations with > or = 30 mg/m(3); and persistent abnormal macrophage/fiber clumps in lungs exposed to 45 and 60 mg/m(3), which suggest overloading of clearance mechanisms. For the chronic study, hamsters were exposed for 78 wk to MMVF10a (901 fiber glass) or MMVF33 (special-application 475 fiberglass) at approximately 300 WHO fibers/cm(3) ( approximately 100 fibers/cm(3) @gt;20 @mu;m long), or to amosite asbestos at an equivalent concentration and 2 lower concentrations. All fiber-exposed animals had pulmonary inflammation, elevated lung lavage cells, and increased lung cell proliferation. Between 52 and 78 wk of exposure, lung burdens of all fibers increased at an accelerated rate, suggesting impairment of clearance mechanisms. MMVF33 and amosite induced fibrosis and pleural mesothelioma. These findings substantiate that exposures in the chronic study adequately tested the toxic potential of fiberglass.