Bernard Adkins

Oncogenic response of strain A/J mice to inhaled chemicals

Strain A/J mice were exposed by inhalation for 6 h/d, 5 d/wk, for 6 mo to carbon disulfide, 1,2-dibromoethane, ethylene oxide, naphthalene, nitrogen dioxide, or vinyl chloride. Significant increases in pulmonary adenoma formation were observed following exposure to 300 ppm carbon disulfide; 20 and 50 ppm 1,2-dibromoethane; 70 and 200 ppm ethylene oxide; 10 ppm nitrogen dioxide; and 50, 200, and 500 ppm vinyl chloride compared to control animals. Repeated studies with 1,2-dibromoethane, ethylene oxide, and vinyl chloride gave similarly significant results. Exposure of mice to 30 ppm naphthalene did not elicit a significant adenoma response. Histopathological examination of lungs from animals in these studies revealed multiple alveolar adenomas. Results from earlier studies with these chemicals, using strain A mice and Swiss mice, and bioassay information with rats and mice were compared with these data. These results provide further information for the validation of this in vivo model as a tool for predicting oncogenic potential following chemical exposure.

NAPHTHALENE: A RESPIRATORY TRACT TOXICANT AND CARCINOGEN FOR MICE

AbstractThe toxicologic and carcinogenic potential of naphthalene was studied by exposing groups of male and female B6C3F1 mice to atmospheres containing 0 (75 mice per sex), 70 ppm (75 mice per sex), or 30 ppm (150 mice per sex) of the chemical for 6 h daily, 5 dayslwk for 103 wk. The final mean body weights of mice exposed to naphthalene were similar to those of the controls. The survival of control male mice was significantly lower than that of the exposed males. The lower survival was attributed to wound trauma and secondary infection related to fighting among the group-housed control animals. There was no significant difference in survival between control and exposed female mice. Under the conditions of this 2-yr study, naphthalene was not carcinogenic to male mice. In female mice it caused an increase in the incidence of pulmonary alveolar/bronchiolar adenomas. Naphthalene also caused an increase in the incidence and severity of chronic inflammation, olfactory epithelium metaplasia of hyperplasia of...

Enhancement of experimental respiratory infection following nickel inhalation

Abstract The effects of nickel chloride inhalation on the enhancement of experimentally induced streptococcal infections were studied. Exposure to nickel chloride (499.2 μg Ni/m 3 ) for 2 hr produced significant enhancement in mortality. This response was observed for 24 hr after the nickel chloride exposure. A delayed clearance response of inhaled streptococci, also observed in the nickel-treated mice, supported the mortality data. Several parameters involving pulmonary cells obtained by in situ lavage 24 hr after nickel chloride exposure were also studied; no reduction in total cell yield, viability, or cellular composition was observed. A significant reduction in phagocytic capability, as compared to that of control animal cells, was observed in alveolar macrophages obtained 24 hr after nickel chloride exposure.

Acute exposure of laboratory mice to manganese oxide

An acute inhalation exposure of laboratory mice to respirable Mn3O4 aerosols is described. The generation system consisted of a Wright dust generator which produced 1.40 micrometer aerosols. A non-linear loss of deposited manganese from mouse lungs over the inital 24-hour post-exposure period was observed. Systemic distribution of the manganese was observed in various tissues following exposure.

Increased pulmonary susceptibility to streptococcal infection following inhalation of manganese oxide

Abstract In this study, laboratory mice exposed to manganese oxide aerosols, then infected with airborne Streptococcus pyogenes , showed greater mortality rates than infected control animals. Maximum mortality rates were determined from acute manganese oxide exposures of 2-hr duration. A consistent dose—response relationship was observed between the amount of manganese retained by the mouse lungs and the enhanced mortality rates. The toxicological consequences of the manganese oxide inhalation were also indicated by reduced initial clearance and subsequent enhanced growth of the streptococci in the manganese-exposed animals, compared to those of the control animals. Streptococcal septicemia occurred earlier in manganese-exposed mice than in control mice, paralleling the increase in subsequent mortality. Immunity against streptococci did not counteract the toxic effects of manganese oxide inhalation and streptococcal infection.

Studies on the Chronic Toxicity (Inhalation) of Wollastonite in Fischer 344 Rats

AbstractWollastonite is a naturally occurring calcium metasilicate acicular mineral that is used in a variety of commercial applications and has been proposed as an asbestos substitute for selected products. Male Fischer 344 rats were exposed by inhalation to 10 mg/m3 (360 fibers/cm3) wollastonite (NYAD-G) for 6 h/d, 5 d/wk for 12 or 24 mo. They were compared to untreated chamber controls and positive controls [chrysotile asbestos, 70 mg/m3 (-7000 fibers/cm3) for 12 mo]. Six rats from each exposure group were killed after 3, 12, and 24 mo. The remaining rats were held for lifetime observation (until 90% mortality). The results of this study showed that wollastonite was slightly toxic to the lung, producing an alveolar macrophage response that resolved after exposure ceased. There was no evidence of wohstonite-induced neoplasms, although the chrysotile asbestos administered under similar conditions produced a high incidence of bronchoalveolar carcinomas.

Changes in biologic and/or immunologic parameters induced by intratracheal instillation of pregnant mice with benzo(α)pyrene are potentially confounded by anesthesia

Benzo(α)pyrene (B(α)P) is a potent multiorgan carcinogen released into the atmosphere from commercial, domestic, and industrial sources. Studies using animal models have shown that giving B(α)P parenterally to pregnant animals (i.e., dams) led to increased tumor frequency and sensitivity to tumorigenesis in their progeny. The authors’ studies also showed that the progeny of the B(α)P-exposed dams displayed increased deficiencies in cell-mediated and humoral immune functions, changes among T-cell subsets in developing lymphoid tissues, and significant expression of B(α)P-7,8-dihydrodiol-9,10-epoxide (BPDE)-DNA adducts in thymic, splenic, and (fetal) liver tissues. The authors evaluated whether similar biologic/immunologic effects of B(α)P seen earlier in parenterally exposed mouse dams (and offspring) occurred if dams were exposed to B(α)P via the lungs. Pregnant dams were subjected to intratracheal instillation of B(α)P (at 1 mg/ml corn oil, 0.1 ml/instillate) beginning on day 11 of pregnancy (GD 11) and again on GDs 12 and 14. In each case, the dams were anesthetized with metofane. Other dams were left untreated (controls), anesthetized only, or anesthetized and then instilled with vehicle. Effects of the B(α)P exposures included lower dam body weights during gestation, decreased postbirth pup survival, increased pup tumor frequency, and decreased mixed-lymphocyte responses by pup lymphocytes. These studies also revealed that metofane imparted effects on the dams and progeny. These effects equaled the B(α)P treatments alone; in other instances, the metofane had no impact, and thus questions the observed biologic/immunologic effects of B(α)P induced in pregnant mice (and their progeny), which might have been confounded by use of this (or potentially other) anesthesia.

Inhalation exposure technology used for varying exposure modes and profiles in toxicology studies

Current technology used in inhalation toxicology studies employs various exposure modes and concentration profiles. Inhalation exposure modes typically utilize wholebody techniques, whereas other exposure modes include nose- and head-only exposure systems and, in some cases, whole- or partial-lung exposure systems. The latter two conditions are utilized when safety considerations are warranted by the hazardous nature of the chemical or agent being tested, the test substance may be dermally adsorbed, and/or the costs of the chemical used are of concern. Inhalation exposure studies may span several minutes to 24 h of continuous exposure and from one day to the full life span of the animal being tested. Time-varying profile exposures, on the other hand, are typically used to mimic human exposures to chemical agents and, in some cases, to more accurately extrapolate animal toxicity data in assessing human risk. Automation of inhalation exposure systems has expedited the timely operation of both accurate and repeatable profiles, and it has allowed for reexamination of classical time-weighted average concentration information relating to human health concerns. The toxicological assessment of potential health effects resulting from exposure to airborne substances typically involves thorough characterizing of the test agent via acute, subchronic, and chronic toxicity testing.

Failure of carbon disulfide and levothyroxine to modify the cardiovascular response of rabbits to a high-cholesterol diet

Exposure of rabbits for 12 weeks to 300 ppm carbon disulfide (CS2) for 6 h/day, 5 days/week, or to 25 mg/day of thiourea or 2% cholesterol in the diet, or to any combination thereof caused a significant reduction in the concentration of serum thyroxine (T4). The reduction of the concentration of serum T4 in rabbits by the treatments was completely offset by the inclusion of 0.1 mg/day of sodium levothyroxine in the diet. Ingestion of feed containing 2% cholesterol significantly increased the degree of atherosclerosis present in the aortic arch and significantly increased the oil red O positive lipid present in the heart and the aorta, with the aortic arch being the most severely affected. The response of the aorta and the heart to the 2% cholesterol diet was not significantly modified by concurrent exposure to CS2 by inhalation or by treatment with thiourea, a metabolite of CS2. We found no evidence that the development of cardiovascular lesions induced by a 2% cholesterol diet in rabbits was mediated by a mechanism involving a component of hypothyroidism.

Determination of Rodent Urinary Porphyrins

The porphqrinogenic nature of arsine (AsH) gas was investigated in a laboratory animal inhalation toxicity study. An assay of urinary porphyrins was developed to measure the AsH treatment effects in mice. Because of the paucity of published assays on animal porphyrin production, this assay was developed from modifications of a human urinary porphyrin assay. A high-performance liquid chromatographic method was developed for the low levels of six common urinary porphyrins observed in mouse urine without extensive pretreatment of the urine samples. Data are presented for a normal CDI mouse urinary porphyrin excretion pattern. along with percent recoveries from urine samples spiked with porphyrins from 0.10 to 0.40 nmol/ml.