Toxicity of polybrominated biphenyls (PBBs) in Domestic and laboratory animals.

The composition, environmental fate, and effects of the polybrominated biphenyls (Firemaster BP-6 or FF-1) involved in the accidental contamination of cattle feed in Michigan in 1973 are reviewed. Toxic effects referred to in this report are limited to those occurring in domestic and laboratory animals and include general toxicity, neurobehavioral toxicity, immunotoxicity, reproductive toxicity, mutagenicity and carcinogenicity. The absorption, distribution, biotransformation and elimination of these polybrominated biphenyls are discussed along with the interactions with other chemicals and drugs.

Renal tumors in rats given trisodium nitrilotriacetic acid in drinking water for 2 years.

One hundred and ninety-six albino male rats [Crl/COBS CD (SD) BR] were given 1,000 ppm trisodium nitrilotriacetic acid (NTA) in drinking water for 2 years. One hundred and ninety-two control rats were given water without NTA. Animals that had a palpable mass or that appeared clinically ill were killed. All survivors were killed at 704 days. A significantly (P less than 0.05) higher proportion of the NTA-treated rats vs. 11.2% of the controls). The largest difference between the NTA-treated rats and the controls in tumor incidence was associated with renal adenoma. The NTA-treated group contained 25 rats with renal adenomas and 4 with renal adenocarcinomas. Only 5 control rats had renal adenomas; none had renal adenocarcinomas. No statistically significant differences were observed for any of the other tumor types among the NTA-treated rats and the controls. The overall incidence of renal tubular cell hyperplasia and nephritis was similar in the treated and control groups. However, a significantly greater number of NTA-treated rats had more severe grades of hyperplasia. Thus NTA when administered continuously in drinking water at a concentration of 1,000 ppm is tumorigenic to the rat kidney.

Extrapolating carcinogenesis data from animals to humans.

Extrapolation of bioassay data from high to low doses and from laboratory animal to the human is essential for future growth of the chemical industries and the safeguard of human health and th environment. To be effective this process requires a solid data base: Metabolism of the chemicals holds many clues regarding their carcinogenic hazards, and studies in liver, kidney, and the specific target organs and their cellular organelles are needed. Other environmental chemicals may alter the effects of a single pollutant by enzyme induction or inhibition in liver or target organ (in cytosol, endoplasmic reticulum, or nuclear membranes) and may cause shunts to alternate pathways which must be explored at different dose levels. DNA repair needs further exploration with attention to the molecular location of attachment of the electrophile to DNA bases and the ability of the target cell for effective repair. Inhibition of DNA repair by environmental chemicals needs better understanding. The synergistic effects of chemicals contribute to the complexity of proper extrapolation of data. Cocardinogenicity is not a laboratory curiosity but a real-life situation. Specific human genetic defects involving DNA repair or immunologic competence may further complicate the issues and need exploration.

Health effects of coal mining and combustion: carcinogens and cofactors.

Some polynuclear aromatics (PNA) have been found to be potent carcinogens for all tissues and organs of experimental animals that have been exposed to them, but different dose levels are needed for these effects. They have been known for decades to cause cancer at the site of application but also at certain sites distant from the area of contact. Although some hydrocarbons are potent and complete carcinogens, the majority of related hydrocarbons was originally found to be inactive. Since they generally appear together, it was important to know more about their interaction, particularly whether they would synergize, or antagonize. The polycyclic hydrocarbons have been studied by subcutaneous injection, where they prove very potent carcinogens. They are also very active on the skin of mice where they produce cancer on prolonged application. Inhalation studies, require larger doses yielded negative results until particulate matter was introduced which facilitated the development of lung tumors. Although iron oxide dust was used initially, other dusts were also capable of enhancing the response of the tissue to benzo(a)pyrene carcinogenesis. This point is of importance, particularly since the inhalation of PNA in situations of air pollution or coal mining involves particulates, although of a different type. Soot is not a homogenous substance and several factors determine its properties. Soots will lose some of the absorbed chemicals during their residence in air, but they retain their PNAs for long periods of time when they reach the soil. The carcinogenicity of PNAs in the adsorbed state may be completely absent, depending on particle size of the soot and availability of eluting capability of the tissues or cells in contact with the soot. Whenever the carcinogenic polynuclear aromatics can be eluted they will be active in producing cancer if their residence is adequate. There seems to be no reason to assume that a large increase in coal combustion in the future will by necessity lead to greater risks of cancer to the coal miners or the general urban dweller, because activities to be started now can take into consideration the requirements necessary for control of air pollution in mines as well as in cities. If new uses of coal will be developed, it will be a completely different situation, and statements about the carcinogenic risk from coal utilization do not apply there. Although some of the same carcinogenic PNAs are involved in the health hazards from those processes, other carcinogens and also cocarcinogens will be present, and the exposed workers will not have the apparent benefits of adsorption of PNAs on soot.

Tissue differentiation and susceptibility to embryonal tumor induction by ethylnitrosourea in the opossum.

Opossums (Didelphis virginiana Kerr) exposed to 100 mg ENU/kg in single or incremental doses early in postnatal life developed a spectrum of epithelial and mesenchymal neoplasms including several types of embryonal neoplasms not previously induced in laboratory animals. A correlation was apparent to a varying degree between susceptibility to tumor induction and the state of morphologic maturation of the presumed target tissues at the light microscopic level for embryonal tumors of the eye, kidney, and brain. The susceptibility of the opossum eye to an ENU-induced intraocular teratoid medulloepithelioma extended over the period from 1 to between 3 and 4 weeks of age and was correlated with the differentiation of the apparent target cell, the nonpigmented ciliary epithelium of the pars ciliaris retinae. Induction of nephroblastomas was correlated with the presence in the kidney of stem cells (metanephric blastema) through the period from birth to between 6 and 8 weeks of age. Although susceptibility of the opossum brain to ENU induction of gangliogliomas was correlated with the state of differentiation of the germinal matrix from birth to 56 days of age, induction of these tumors was essentially limited to the 1st week postpartum. No definite correlation between vulnerability to tumor induction and tissue maturation was evident for a tumor of the jaw (ameloblastoma) with presumed origin from embryonic dental remnants. Our results indicated that the opossium early in postnatal life is a useful model for the induction and characterization of certain of the major dysontogenetic tumors, which have been difficult or impossible to reproduce in the traditional laboratory species.

Haloethylene-related compounds of industrial, environmental, and medical significance.

A broad-based literature survey was made for chemicals that contain either a haloethylene or a related substructure. Two hundred and sixty-two compounds, including synthetic intermediates, pesticides, solvents, drugs, food components, natural products, and metabolites, are grouped by their structures. Some are in current use or are bioavailable while little exposure is expected from others. As more biologic-response information is reported for small compounds of these types, it should become possible to select others for research on additional questions of structure-activity relationships. Some of the compounds are widespread while others are not. Some are used or found in large amounts while others may be trace contaminants, minor or more major by-products of synthesis or isolation. The pesticides and solvents, for example, are knowingly and often deliberately released to the environment, sometimes in very large quantities. Inadvertent release also occurs, sometimes referred to as fugitive emission. Food contaminants and drugs are directly accessible to humans. Sparsely distributed natural products could be accessible to humans, for example, via the food chain. Some of the compounds in food may be formed during preparation, storage or metabolically. Last, the haloethylene function has often been synthesized into compounds in order to achieve desired biologic activities. There are many types and degrees of relatedness of structure, depending upon atomic dimensions and stereochemical, polar, resonance, and other factors. Furthermore, for some chemical series, biologic responses are continuously variable while, in other cases, it is not uncommon that qualitatively different types of response occur with apparently very close homologs. Genetic, metabolic, and behavioral factors affecting response must also be considered. Thus, safety or hazard cannot yet be predicted conclusively by apparent relatedness of structure alone. Also, since the tables are noncomprehensive, some relevant compounds have likely been omitted. The haloalkanes, for example, are not here because of their large number, despite the knowledge that some are either metabolized or nonbiologically converted to haloalkenes.

Embryonal neoplasms in the opossum: a new model for solid tumors of infancy and childhood.

Opossums fed the chemical carcinogen ethyl nitrosourea early in postnatal life developed a variety of epithelial and mesenchymal embryonal neoplasms that were closely analogous, in morphology and biological behavior, to tumors of human infancy and childhood for which experimental models in laboratory animals are either imprecise or nonexistent. The embryonal tumors were found in association with, and occasionally at the same sites as, a limited number of malformations.

Possible mechanisms of combination effects in chemical carcinogenesis.

In order to understand variations in thresholds to chemical carcinogens, it is important to appreciate, besides the genetic determinants, those many environmental factors which are at play, at all times, modifying the thresholds for chemical carcinogenesis. An understanding of the mechanisms of action of these factors may make it possible to tackle the difficult problem of determining human threshold levels.

Editorial: Considerations of risks versus benefits.

An evaluation of risks versus benefits from new products should be encouraged, even when dealing with agents which may cause cancer or malformations in laboratory animals, because there is evidence that safety thresholds exist even for such exposures. However, it is not easy to describe risk and benefit in comparable terms when they may involve generations to come and events in the future.

Inhalation studies of nickel sulfide in pulmonary carcinogenesis of rats.

Two hundred twenty-six specific pathogenfree male and female F344 rats were exposed to nickel sulfide inhalations for 78 weeks (5 days/wk, 6 hr/day) and observed for an adiditional 30-week period. For the same amount of time, 214 rats were exposed to filtered room air and served as controls. Rats exposed to nickel sulfide showed a significantly higher incidence of pulmonary hyperplastic and neoplastic lesions originating from the bronchial and bronchiloo-alveloar segments. The overall incidence of lung tumors in the animals treated with nickel sulfide was 14 percent compared with 1 percent in the controls. Pulmonary inflammatory reactions were also greatly increased. Injection of an agent (hexachlorotetra-fluorobutane) that induced lung infarction did not increase the proportion of animals having lesions, nor did it alter the type of lesions found in animals exposed to nickel sulfide.

Teratogenic evaluation of 2,4,5-T.

The herbicide 2,4,5-trichlorophenoxyacetic acid is teratogenic and fetocidal in two strains of mice when administered either subcutaneously or orally and in one strain of rats when administered orally. The incidences of both cystic kidney and cleft palate were increased in the C57BL/6 mice as well as the incidence of cleft palate in the AKR mice. The incidence of cystic kidney was also increased in the rats. In addition, an increase in the ratio of liver weight to body weight in the mouse fetus and the occurrence of hemorrhagic gastrointestinal tract in the rat fetus suggest that this compound also has fetotoxic properties.