Robert T. Drew

Current Concepts of Chronic Benzene Toxicity

AbstractThe maladies that have beset mankind throughout history may in general be classified as parasitic (infections, infestations, etc.), nutritional/endocrine disease (hyper- or hypofunctional endocrine organs, etc.), or traumatic injury (accidents, war, etc.). With the development of an industrial society, new forms of disease arose in which people succumbed to illness induced by exposure to toxic materials in the course of their labor. Occupational diseases have been with us for many centuries,1, 2 but the incidence of industrial toxicity increased markedly with the advent of the industrial revolution. Although efforts to protect workers against job-related illness have been vigorous in recent years, economic necessity compels the continued use of hazardous chemicals, and benzene is an excellent case in point. It has been estimated by the National Institute for Occupational Safety and Health that about 2, 000, 000 persons in the national work force have potential exposure to benzene.

Tumors of the Respiratory Tract Induced by Inhalation of Bis(Chloromethyl)Ether

Squamous ceil carcinomas of the lung and esthesioneuroepitheliomas of the olfactory epithelium were produced in high incidence in rats following inhalation of 0.1 ppm of bis(chloromethyl)ether. These findings imply a significant potential occupational hazard.

The effect of age and exposure duration on cancer induction by a known carcinogen in rats, mice, and hamsters

Female Golden Syrian hamsters, F-344 rats, Swiss CD-1 mice, and B6C3F1 hybrid mice were exposed 6 hr/day, 5 days/week to carcinogenic levels of vinyl chloride (VC) for 6, 12, 18, or 24 months (rats and hamsters only). Other groups of rodents were held for 6 or 12 months and then exposed for 6 or 12 months. At the end of the study the incidence of VC-induced neoplasms was compared in each of the groups to assess the effects of duration of exposure and age at the start of exposure on carcinogenicity of VC. In rats, with early initial exposure, hemangiosarcomas, hepatocellular carcinomas, and mammary gland carcinomas occurred with increasing incidence with longer exposure duration. Rats held for 6 months before exposure developed VC-related neoplasms, while rats held 12 months before the start of exposure failed to show a significantly increased incidence of these neoplasms. In hamsters, hemangiosarcomas, mammary gland carcinomas, gastric adenocarcinomas, and skin carcinomas resulted from VC exposure. The highest incidence of malignant neoplasms occurred in hamsters exposed for the first 12 months, whereas exposure begun after 12 months of age did not cause neoplasms. In both strains of mice, VC exposure during the first 6 months of the experiment induced a high incidence of hemangiosarcomas and mammary gland carcinomas. Swiss mice also developed lung carcinomas after only 6 months of exposure. In all three rodent species an initial 12 month exposure to VC was adequate to detect its carcinogenic potential, but the shortened survival of VC exposed mice and hamsters precluded a meaningful comparison with longer periods of exposure. Exposures were most effective when started early in life.

Inhalation carcinogenicity of alpha halo ethers. III. Lifetime and limited period inhalation studies with bis(chloromethyl)ether at 0.1 ppm.

Rats and hamsters were exposed to 0.1 ppm bis(chloromethyl)ether (BCME) six hours per day, five days per week throughout their lifetime. Additional groups of rats were given 10, 20, 40, 60, 80, and 100 exposures to 0.1 ppm BCME and then held until death. Forty cancers originating in the respiratory tract were found in the 200 rats involved in these studies. These included 14 cancers of the lung and 26 cancers of the nasal cavity. They occurred in dose-related fashion. A single undifferentiated carcinoma of the lung was seen in a hamster.

The lack of effects of pretreatment with phenobarbital and chlorpromazine on the acute toxicity of benzene in rats

Abstract Female CD rats were injected ip daily for 3 days with either phenobarbital (75 mg/kg) or chlorpromazine (15 mg/kg). On the fourth morning the animals were either subjected to a 4-hr inhalation exposure of benzene or given an ip injection of 50% ( v v ) of benzene and mineral oil. Animals were injected with doses of 1, 2, 3 and 4 g benzene/kg body weight. In the inhalation studies, animals were exposed to 6 levels of benzene ranging from 11,500 to 15,500 ppm. The LD50 for animals injected with benzene and the LC50 for animals inhaling benzene were calculated for control groups and those pretreated with either phenobarbital or chlorpromazine. Neither the LD50 or the LC50 were affected by any of the treatment protocols. In order to determine that the pretreatment was stimulating benzene metabolism, a method for measuring benzene metabolism has been developed using [14C]benzene. These studies have shown that phenobarbital and 3-MC do induce benzene metabolism in the liver, that chlorpromazine slightly induces benzene metabolism in the lung, and that pretreatment by these compounds does not affect the acute inhalation toxicity or the ip toxicity of benzene.

Inhalation exposure methodology.

Modern man is being confronted with an ever-increasing inventory of potentially toxic airborne substances. Exposures to these atmospheric contaminants occur in residential and commercial settings, as well as in the workplace. In order to study the toxicity of such materials, a special technology relating to inhalation exposure systems has evolved. The purpose of this paper is to provide a description of the techniques which are used in exposing laboratory subjects to airborne particles and gases. The various modes of inhalation exposure (whole body, head only, nose or mouth only, etc.) are described at length, including the advantages and disadvantages inherent to each mode. Numerous literature citations are included for further reading. Among the topics briefly discussed are the selection of appropriate animal species for toxicological testing, and the types of inhalation studies performed (acute, chronic, etc.).

Inhalation carcinogenicity of alpha halo ethers. I. The acute inhalation toxicity of chloromethyl methyl ether and bis(chloromethyl) ether.

A range of acute studies were performed with chloromethyl methyl either (CMME) and bis(chloromethyl)ether (BCME), including 14-day LC50s following single seven-hour inhalation exposures. The LC50s for CMME were 55 ppm for rats and 65 ppm for hamsters. The LC50s for BCME were 7 ppm for both species. All animals showed characteristic changes of acute irritation of the respiratory tract manifested by congestion, edema, and hemorrhage. Severe shortening of life span was seen in 30-day exposures of rats to CMME and in all studies with BCME. Incidences of mucosal changes, including atypia, were generally increased in a dose-related manner in both species. The carcinogenicity of BCME in these range finding experiments was demonstrated by a skin cancer in a rat after three exposures and a nasal tumor in a hamster after one exposure to 1 ppm BCME.

Changes in serum enzymes in rats after inhalation of organic solvents singly and in combination

Abstract Using death as an endpoint, it has been demonstrated that tetrachloroethylene (TCE) produces a greater-than-additive effect when given orally in combination with several other compounds. We have attempted to determine more sensitive indicators which would respond in a synergistic fashion when animals are exposed by inhalation to combinations of organic solvents. Male rats were exposed for 4 hr to various concentrations of TCE, dioxane, butyl ether (BE), acetonitrile (ACN), trichloropropane (TCP), and dichloropropane (DCP). The serum enzymes, glutamic oxalacetic transaminase (SGOT), glutamic pyruvic transaminase (SGPT), glucose-6-phosphatase (G-6-Pase), and ornithine carbamyl transferase (OCT) were measured in rats prior to exposure, immediately after exposure, and at 24 and 48 hr after exposure. The enzymes, SGOT, SGPT and OCT, were markedly elevated as a result of exposure to the above compounds, whereas G-6-Pase was only occasionally altered. Neither TCE in combination with dioxane, BE, or ACN nor TCP with DCP resulted in a greater-than-additive effect. On the contrary, in many instances the effects were significantly less-than-additive when tested for interaction.

Dichloromethane inhalation, carboxyhemoglobin concentrations, and drug metabolizing enzymes in rabbits

Abstract The relationship between inhaled dichloromethane (DCM) and percentage of carboxyhemoglobin (% COHb) in blood has been investigated in rabbits. After a single 20-min exposure to DCM, % COHb rose to a maximum within 2–3 hr and usually declined to basal values within 8 hr. The maximum COHb concentration and the time to reach that value were DCM concentration-dependent. In rabbits given a 4-hr exposure to DCM, % COHb increased over the first 2–3 hr, reaching a peak by about 4 hr with a return to basal levels within 24 hr. Studies were carried out to determine whether treatment with modifiers of hepatic mixed-function oxidase changed the % COHb response after DCM exposure. Of the compounds investigated, only CCl 4 and phenobarbital altered % COHb resulting from DCM inhalation. As expected, CCl 4 , a potent hepatotoxin, reduced the % COHb resulting from DCM inhalation. Contrary to expectations phenobarbital also lowered the COHb response from DCM inhalation although the decrease was not as marked as that caused by CCl 4 .

Inhalation Studies With a Glycol Complex of Aluminum-Chloride-Hydroxide

Inhalation studies were performed with a propylene glycol complex of aluminum-chloride-hydroxide (alchlor), a compound found in some aerosol antiperspirant preparations. Hamsters were given either three exposures to 150 mg alchlor/cu meter or 30 exposures to 50 mg/cu meter and killed at various times for histopathological examination. The lungs of animals given 20 or more exposures to 50 mg/cu meter showed a granulomatous lesion in the respiratory bronchioles that persisted throughout a six-week postexposure period. Alveolar thickening and increased numbers of macrophages were seen in lungs of hamsters soon after three exposures to 150 mg/cu meter but with time these changes regressed. Lung weights in hamsters given three exposures to 35 mg/cu meter or higher were increased on the fourth day. Mixed function oxidase (MFO) activities of rabbit and hamster microsomes from both lung and liver were examined after three daily exposures. No changes were seen in the MFO activity of liver microsomes. Lung microsom...