Showing papers in "Environmental Health Perspectives in 1982"

Pharmacokinetics, interactions with macromolecules and species differences in metabolism of DEHP.

Abstract: The recent long-term carcinogenesis bioassay of di(2-ethylhexyl) phthalate (DEHP) in rats and mice reported by the National Toxicology Program was the first such bioassay to implicate DEHP as a hep...

Testicular Effects of Phthalate Esters

Abstract: The testicular effects produced by di(2-ethylhexyl) phthalate (DEHP) in the rat, characterized by a decrease in the relative organ weight and histological changes in the seminiferous tubules, can also be produced by di-n-butyl, di-n-pentyl and di-n-hexyl phthalates. The corresponding monoesters of these compounds, formed in vivo as a result of the action of nonspecific esterases in the intestinal mucosa and other tissues, were equally effective in inducing testicular damage. Phthalate-induced testicular injury was accompanied by a decrease in the zinc content in the gonads and in increased urinary excretion of this element. Exposure of preparations of rat seminiferous tubule cells in culture to monophthalates capable of producing testicular injury resulted in a dose-related detachment of germinal cells from Sertoli cells in a manner similar to the effect seen in the intact animal. This in vitro system may find application in the elucidation of the toxic mechanisms involved in phthalate-induced testicular injury and in screening compounds likely to act in a manner similar to phthalates.

Carcinogenicity testing of phthalate esters and related compounds by the National Toxicology Program and the National Cancer Institute.

Abstract: Five phthalate ester and related compounds (phthalic anhydride, phthalamide, di(2-ethylhexyl) phthalate, di(2-ethylhexyl) adipate and butyl benzyl phthalate) have been tested for carcinogenic effec...

Overview of phthalate ester pharmacokinetics in mammalian species.

Abstract: Phthalic acid esters, or phthalate esters, are generally well absorbed from the gastrointestinal tract following oral administration. Hydrolysis to the corresponding monoester metabolite, with release of an alcoholic substituent, largely occurs prior to intestinal absorption of the longer-chain alkyl derivatives such as di(2-ethylhexyl) phthalate (DEHP). Phthalate esters are widely distributed in the body, with the liver being the major, initial repository organ. Clearance from the body is rapid and there is only a slight cumulative potential. Short-chain dialkyl phthalates, such as dimethyl phthalate, can be excreted in an unchanged form or following complete hydrolysis to phthalic acid. Longer-chain compounds such as DEHP, however, are converted principally to polar derivatives of the monoesters by oxidative metabolism prior to excretion. A marked species difference in DEHP metabolism exists: primates (man, monkey, some rodent species) glucuronidate DEHP at the carboxylate moiety following hydrolysis of a single ester linkage, whereas rats appear to be unable to glucuronidate the monoester metabolite and oxidize the residual alkyl chain instead to various ketone and carboxylate derivatives. The major route of phthalate ester elimination from the body is urinary excretion. Certain phthalate esters are excreted in the bile but undergo enterohepatic circulation. The relationships of phthalate ester pharmacokinetics to their toxicological actions are unknown at the present time, largely due to a lack of elucidated mechanisms of toxic action.

Toxic potential of the plasticizer Di(2-ethylhexyl) phthalate in the context of its disposition and metabolism in primates and man.

Abstract: Although human toxicity from exposure to the plasticizer di(2-ethylhexyl) phthalate (DEHP) is unknown, reports of animal toxicity from DEHP have stimulated extensive toxicological studies. In the a...

Phthalate esters as peroxisome proliferator carcinogens.

Abstract: The phthalate ester di(2-ethylhexyl) phthalate is both a peroxisome proliferator and a hepatic carcinogen. Peroxisome proliferators as a class are hepatocarcinogenic in rodent species. However, none of the peroxisome proliferators tested to date including the phthalate esters and related alcohol and acid analogs have demonstrated mutagenic or DNA-damaging activity in the in vitro Salmonella typhimurium/microsomal or the lymphocyte 3H-thymidine assays. A working hypothesis is proposed that peroxisome proliferation itself initiates neoplastic transformation of hepatic parenchymal cells by increasing intracellular rates of DNA-damaging reactive oxygen production. Evidence which supports such a hypothesis includes increased fatty acid beta-oxidation, elevated H2O2 levels, accumulation of peroxidized lipofuscin, disproportionately small increase in catalase, and elevated peroxisomal uricase activity which accompany peroxisome proliferation in hepatocytes. Direct testing of this hypothesis will provide insight into mechanisms of phthalate ester carcinogenicity and cytotoxicity.

Toxicological effects of chlorine dioxide, chlorite and chlorate.

Abstract: Review of the available literature obtained from both acute and chronic experiments utilizing rats, mice and chickens treated with ClO2, ClO2- and ClO3-in drinking water has demonstrated alterations in hematologic parameters in all species tested. The effects were usually dose related and marked changes occurred only at the higher dosages (up to 1000 mg/l.). In chronic studies, rats have been given ClO2 at doses of up to 1000 mg/l., and NaClO2 or NaClO3 at up to 100 mg/l., in their drinking water for one year. Treatment groups receiving ClO2, ClO2- or ClO3- showed alterations in erythrocyte morphology and osmotic fragility; at higher dosages mild hemolytic anemia occurred. An examination of blood glutathione content and RBC enzymes involving glutathione formation showed a dose-related diminution of glutathione in chlorine compound treated groups. The higher oxidative capacity of the chlorine compounds resulting in the decreased erythrocytic glutathione might well be the principal biochemical event leading to the other hematological alterations. More recent data show that ClO2, ClO2- and ClO3- alter the incorporation of 3H-thymidine into the nuclei of various organs of the rat. These data suggest the possibility of increased turnover cells of the gastrointestinal mucosa and inhibited DNA synthesis in several organs. In the latter category, most concern revolves around whether or not the apparent depression of DNA synthesis in the testes is associated with depressed spermatogenesis and reproductive toxicity in the male rat.

Chemotherapy-induced immunosuppression.

Abstract: Chemotherapeutic agents are used widely in clinical medicine for the treatment of conditions where diminution of the host immune response is a goal. The clinical use of immunosuppression is indicated for immunologically mediated disease, lymphoproliferative diseases, and prevention of graft rejection. Five categories of agents are useful for these purposes; they are ionizing irradiation, corticosteroids, biological alkylating agents, antilymphocyte sera and antimetabolites. While the specific molecular action of many of these drugs is known, how they affect cellular events in immune responses is less clear. One of the unfortunate sequelae of chemotherapy induced immunosuppression is an increased susceptibility of the host to opportunistic pathogens or malignancies. Specific methods are described for monitoring the various parameters of both humoral and cellular immunity. Studies of immunologic function in lymphoma patients and cardiac transplant patients treated with immunosuppressive drugs have shown specific defects in cell mediated immunity to herpes viruses which may relate to their increased susceptibility to infection by these agents.

Teratogenicity of di(2-ethylhexyl) phthalate (DEHP) and di-n-butyl phthalate (DBP) in mice.

Abstract: Di(2-ethylhexyl) phthalate (DEHP) and di-n-butyl phthalate (DBP) were mixed with diet at graded levels of 0.05, 0.1, 0.2. 0.4 and 1.0 wt-% and given to pregnant ICR mice throughout gestation. Maternal weight gain was suppressed and fetal resorption increased at 0.2, 0.4 and 1.0% levels of DEHP and 1.0% level of DBP. All the implanted ova died early in rats fed 0.4 and 1.0% levels of DEHP. External malformations increased significantly by 0.2% DEHP, and 1.0% DBP showed borderline significance. The major malformations in treated groups were neural tube defects (exencephaly and myeloschisis), suggesting that the phthalic acid esters (PAEs) affect neural tube closure in developing embryos. Treatment with the compounds caused intrauterine growth retardation and delayed ossification with an apparently dose-related response pattern. These results indicate that a high dose of DEHP and DBP might be embryotoxic and teratogenic in mice. The maximum nonembryotoxic doses of PAEs in mice were more than 2000 times the estimated level of human intake through the food chain. Thus it is assumed that the current "normal" exposure level of PAEs dose not pose an imminent threat to human fetal development.

Occurrence of arsenic in plaice (Pleuronectes platessa), nature of organo-arsenic compound present and its excretion by man.

Abstract: The arsenic content in 255 samples of plaice (Pleuronectes platessa) varied between 3 and 166 mg/kg. About 65% of the samples had an arsenic content above 10 mg/kg. High (low) arsenic concentration...

Mutagenic/carcinogenic potential of DEHP and MEHP.

Abstract: The mutagenic/carcinogenic activities of DEHP and MEHP were studied in bacteria and mammalian cells. MEHP but not DEHP exerted a dose-dependent DNA damaging effect to B. subtilis in Rec-assay. DEHP...

Assessment of the mutagenicity of phthalate esters.

Abstract: The Ames assay was used to investigate the mutagenicity of several phthalate esters as an approximation of their carcinogenic potential. The ortho diesters, dimethyl phthalate (DMP) and diethyl pht...

Effects of phthalate esters on lipid metabolism in various tissues, cells and organelles in mammals.

Abstract: The effect of phthalate ester plasticizers on a variety of enzyme systems was studied in rats, rabbits and pigs. The feeding of di(2-ethylhexyl) phthalate (DEHP) to animals at levels from 0.1% to 1.0% in the diet resulted in diverse biochemical effects, such as inhibition of cholesterologenesis in liver, testes, and adrenal gland; inhibition of cholesterologenesis in brain and liver of fetal rats from DEHP-fed dams; decreased plasma cholesterol levels; decreased synthesis of hepatic phospholipid and triglyceride; increased fatty acid oxidation in isolated liver mitochondria; and a transient decrease in fatty acid oxidation in isolated heart mitochondria. The addition of DEHP to preparations of rat liver in vitro resulted in inhibition of cholesterologenesis, and its addition to isolated mitochondria from rat heart produced an inhibition of adenine nucleotide translocase. DEHP-feeding to rats and rabbits, however, did not affect platelet function as judged by collagen- and ADP-induced aggregation. The studies presented here indicate that the exposure of animals to phthalate esters can result in a significant perturbation of normal metabolism in liver, heart, testes, adrenal gland and brain and can affect blood lipid levels.

Presence, introduction and removal of mutagenic activity during the preparation of drinking water in the Netherlands.

Abstract: A survey of the presence of mutagenic activity in drinking water of 18 cities in the Netherlands revealed that in drinking water of 13 cities mutagenic activity could be demonstrated. The activity ...

Subchronic toxicity of chlorine dioxide and related compounds in drinking water in the nonhuman primate.

Abstract: Subchronic toxicities of ClO2, NaClO2, NaClO3 and NH2Cl were studied in the African Green monkeys (Cercopithecus aethiops). The chemicals were administered in drinking water during 30-60 days subchronic rising dose protocols. The only unexpected and significant toxic effect was elicited by ClO2; this chemical inhibited thyroid metabolism in the animals at a dose of ca. 9.0 mg/kg/day. A statistically significant decrease of serum thyroxine occurred after the fourth week of exposure to 100 mg/l.concentration. The extent of thyroid suppression was dose dependent in each individual monkey, and was reversible after cessation of exposure. NaClO2 and NaClO3 failed to elicit similar effects in doses up to ca. 60 mg/kg/day. Also, NaClO4 or NH2Cl did not cause T-4 suppression in doses of 10 mg/kg/day. The selective thyroid effect of ClO2 was unexplained and it appeared to be paradoxical since ClO2 was rapidly reduced by the oral and gastric secretions to nonoxidizing species (presumably Cl-). No evidence of thyroid effects were detected in the serum of human volunteers who ingested approximately 1 mg/l. of ClO2 in drinking water as a result of routine use in the community water treatment process. Sodium chlorite induced dose-dependent oxidative stress on hematopoesis, causing decreased hemoglobin and red cell count and increased methemoglobin content. At the same time, serum transaminase (SGPT) levels showed significant subclinical elevation. The hematologic effects of NaClO2 rebounded during exposure indicating compensatory hemopoietic activity taking effect during oxidative stress. Sodium chlorate and chloramine did not induce detectable hematologic changes in the animals.

Hepatic effects of phthalate esters.

Abstract: Di(2-ethylhexyl) phthalate (DEHP), a commonly used plasticizer and microchemical environmental pollutant, produces subtle changes in hepatic function as judged by increase in liver weight and morphological and biochemical alterations. It can modify the biological response of drugs and other xenobiotics. Such interactions appear to occur at the pharmacokinetic phase, as DEHP was found to alter the activity of microsomal drug-metabolizing enzymes and ethanol metabolism. DEHP produced a time- and route-dependent effect on the hepatic cytochrome P-450 contents and activity of aminopyrine N-demethylase, aniline hydroxylase, alcohol dehydrogenase and high and low Km aldehyde dehydrogenases when given orally or intraperitoneally. Under in vitro conditions, DEHP produced no effect on the activity of aminopyrine N-demethylase or aniline hydroxylase, while mono(2-ethylhexyl) phthalate (MEHP) and 2-ethylhexanol (2-EH) significantly inhibited their activity at concentrations ranging from 2.5 to 15.0 mM. Activity of aminopyrine N-demethylase and aniline hydroxylase was also inhibited by dimethyl phthalate (DMP) and dibutyl phthalate (DBP) after a single oral administration. In view of the possibility of the human exposure to phthalates and other xenobiotics simultaneously, these observations are of great significance.

Risk assessment in a federal regulatory agency: an assessment of risk associated with the human consumption of some species of fish contaminated with polychlorinated biphenyls (PCBs).

Abstract: The problem of polychlorinated biphenyls (PCBs) became a national concern in 1971 when several accidental contaminations of foods were reported. Extensive efforts were undertaken by FDA to reduce the residues of PCBs in food. However, the PCB levels in several species of fresh-water fish have raised concern about the PCB residues from environmental contamination, and it is this concern which has prompted a reassessment of the human risk involved from consumption of such fish. The human epidemiology and animal toxicity of PCB exposure are reviewed, as well as risk assessment in general. Specific examples to risk assessment involving extrapolation of animal data to humans, based on several levels of human exposure to PCBs in fish, are presented.

Mutagenic activity associated with by-products of drinking water disinfection by chlorine, chlorine dioxide, ozone and UV-irradiation.

Abstract: A retrospective epidemiological study in The Netherlands showed a statistical association between chlorination by-products in drinking water and cancer of the esophagus and stomach for males. A pilot-plant study with alternative disinfectants was carried out with stored water of the Rivers Rhine and Meuse. It was demonstrated that the increase of direct acting mutagens after treatment with chlorine dioxide is similar to the effect of chlorination. Ozonation of Rhine water reduced the mutagenic activity for Salmonella typhimurium TA 98 both with and without metabolic activation. UV alone hardly affects the mutagenicity of the stored river water for S. typh. TA 98. In all studies, practically no mutagenic activity for S. typh. TA 100 was found. Although remarkable changes in the concentration of individual organic compounds are reported, the identity of the mutagens detected is yet unclear. Compounds of possible interest due to their removal by ozonation are 1,3,3-trimethyloxindole, dicyclopentadiene and several alkylquinolines. Compounds which might be responsible for the increased mutagenicity after chlorination are two brominated acetonitriles and tri(2-chlorethyl) phosphate. Furthermore, the concentration procedure with adsorption on XAD resin and the subsequent elution step may have affected the results. It is proposed to focus further research more on the less volatile by-products of disinfection than on the trihalomethanes.

Reaction products of aquatic humic substances with chlorine.

Abstract: A major concern of the chlorination of aquatic humic materials is the ubiquitous production of trihalomethanes. A large number of other chlorinated organic compounds, however, have been shown to be...

Embryology of the eye.

Abstract: A brief description of the basic patterns of mammalian development of the eye is presented based on events as they occur in human beings. The emphasis is not on the details of this development, but rather on its organization and timing, with a figure of comparative development providing a comparison of similar events in man, rat, mouse, and chick.

Reaction products of chlorine dioxide.

Abstract: Inspection of the available literature reveals that a detailed investigation of the aqueous organic chemistry of chlorine dioxide and systematic identification of products formed during water disinfection has not been considered This must be done before an informed assessment can be made of the relative safety of using chlorine dioxide as a disinfectant alternative to chlorine Although trihalomethanes are generally not formed by the action of chlorine dioxide, the products of chlorine dioxide treatment of organic materials are oxidized species, some of which also contain chlorine The relative amounts of species types may depend on the amount of chlorine dioxide residual maintained and the concentration and nature of the organic material present in the source water The trend toward lower concentrations of chlorinated by-products with increasing ClO2 concentration, which was observed with phenols, has not been observed with natural humic materials as measured by the organic halogen parameter Organic halogen concentrations have been shown to increase with increasing chlorine dioxide dose, but are much lower than those observed when chlorine is applied Aldehydes have been detected as apparent by-products of chlorine dioxide oxidation reactions in a surface water that is a drinking water source Some other nonchlorinated products of chlorine dioxide treatment may be quinones and epoxides The extent of formation of these moieties within the macromolecular humic structure is also still unknown

Hepatic effects of a phthalate ester plasticizer leached from poly(vinyl chloride) blood bags following transfusion.

Abstract: The effects of di(2-ethylhexyl) phthalate (DEHP) on hepatic function and histology were evaluated in the rhesus monkey undergoing platelet and plasma transfusion. The average cumulative amount infused in one year is comparable to that received by patients who undergo chronic transfusion. Abnormalities in hepatic scan and BSP kinetics persisted for up to 26 months after transfusion, as did histologic abnormalities. Patients undergoing maintenance hemodialysis receive a yearly dose of DEHP which is 10-20 times that which produced hepatotoxicity in the transfused rhesus.

Mutagenic activity of phthalate esters in bacterial liquid suspension assays.

Abstract: The mutagenic activities of several phthalate esters have been evaluated in an 8-azaguanine resistance assay in Salmonella typhimurium. Three phthalate esters were found to be mutagenic: dimethyl phthalate, diethyl phthalate and di-n-butyl phthalate. A number of other phthalate esters were not found to be mutagenic, including di(2-ethylhexyl) phthalate, di-n-octyl phthalate, diallyl phthalate, diisobutyl phthalate and diisodecyl phthalate. A metabolite of di(2-ethylhexyl) phthalate, 2-ethylhexanol, was also noted to be mutagenic. The mutagenic activity of this agent and others in this series was dose dependent but weak. No dose-response curve exceeded more than 3.5 times background at maximally testable concentrations. A liquid suspension histidine reversion assay of dimethyl phthalate showed levels of mutagenic activity similar to that observed in the azaguanine resistance assay. The data suggest a need for further investigation of the mutagenic potential of these agents in other assay systems.

Waterborne outbreak control: which disinfectant?

Abstract: Drinking water disinfection was shown to be an important public health measure around the turn of the century. In the United States, it was perhaps the single most important factor in controlling typhoid fever, a waterborne disease that was rampant throughout the world during the last century. It may also be assumed that disinfection was important in limiting the number of cases of other diseases known to be capable of waterborne transmission, i.e., cholera, amebiasis, shigellosis, salmonellosis, and hepatitis A. Even though modern treatment has eliminated water as a major vehicle of infectious disease transmission, outbreaks still occur. In fact, the annual number has been increasing since 1966. Interruption in chlorination or failure to achieve adequate levels of chlorine residual is the most often identified deficiency of the involved water supplies. This finding indicates that waterborne microbial pathogens remain as a potential health threat and underscores the importance of disinfection. From the outset, chlorination has been the drinking water disinfectant of choice in the country. Numerous studies have demonstrated its ability to inactivate bacterial, viral, and protozoal pathogens when applied under proper conditions. However, the finding that chlorinated organics that are potentially carcinogenic are formed has prompted an evaluation of alternative disinfectants. The viable alternatives to chlorine currently under consideration for widespread use are ozone, chlorine dioxide, and chloramines. In terms of biocidal efficiency, ozone is the most potent of the three. Chlorine dioxide is about the equivalent of free chlorine in the hypochlorous acid form but much more efficient than the hypochlorite form of free chlorine. The chloramines are weaker biocides than hypochlorite. Although this general order of ranking of efficiency holds for diverse types of microorganisms, quantitative comparisons vary with different microorganisms and experimental conditions.

Phthalate ester testing in the National Toxicology Program's environmental mutagenesis test development program.

Abstract: A number of phthalate esters and related chemicals were tested for mutagenicity in Salmonella typhimurium. The chemicals were tested blind in three laboratories by a preincubation modification of the Ames Salmonella/mammalian microsome test using S-9 prepared from Aroclor-induced rats and Syrian hamsters. All chemicals tested were judged to be nonmutagenic.

Controlled Clinical Evaluations of Chlorine Dioxide, Chlorite and Chlorate in Man

Abstract: To assess the relative safety of chronically administered chlorine water disinfectants in man, a controlled study was undertaken. The clinical evaluation was conducted in the three phases common to investigational drug studies. Phase I, a rising dose tolerance investigation, examined the acute effects of progressively increasing single doses of chlorine disinfectants to normal healthy adult male volunteers. Phase II considered the impact on normal subjects of daily ingestion of the disinfectants at a concentration of 5 mg/l. for twelve consecutive weeks. Persons with a low level of glucose-6-phosphate dehydrogenase may be expected to be especially susceptible to oxidative stress; therefore, in Phase III, chlorite at a concentration of 5 mg/l. was administered daily for twelve consecutive weeks to a small group of potentially at-risk glucose-6-phosphate dehydrogenase-deficient subjects. Physiological impact was assessed by evaluation of a battery of qualitative and quantitative tests. The three phases of this controlled double-blind clinical evaluation of chlorine dioxide and its potential metabolites in human male volunteer subjects were completed uneventfully. There were no obvious undesirable clinical sequellae noted by any of the participating subjects or by the observing medical team. In several cases, statistically significant trends in certain biochemical or physiological parameters were associated with treatment; however, none of these trends was judged to have physiological consequence. One cannot rule out the possibility that, over a longer treatment period, these trends might indeed achieve proportions of clinical importance. However, by the absence of detrimental physiological responses within the limits of the study, the relative safety of oral ingestion of chlorine dioxide and its metabolites, chlorite and chlorate, was demonstrated.

Teratogenicity/fetotoxicity of DEHP in mice.

Abstract: The embryonic/fetotoxic effects of DEHP on pregnant mice (ddY-Slc female x CBA male) were studied. DEHP was administered orally in dosages of 0.05 ml/kg to 30.0 mg/kg on day 6, 7, 8, 9 or 10 of gestation. A single administration of DEHP over 0.1 ml/kg (1/300 of LD50) on day 7 of gestation decreased the numbers and the body weight of living fetuses, whereas no significant changes in the numbers of living fetuses (with no gross and skeletal abnormalities) were observed compared with those of the control group, when 0.05 ml/kg (1/600 of LD50) of DEHP was administered. The fetotoxicity (fetal death) was dose dependent. The LD50 and the nonfetolethal maximum dosage of DEHP in its single, oral administration was 592 mg/kg and 64 mg/kg, respectively. The latter value is much higher than an estimated DEHP intake from commercial foodstuffs in men, which is approximately 0.03 mg/kg/day.

Use of biological assay systems to assess the relative carcinogenic hazards of disinfection by-products.

Abstract: Other workers have clearly shown that most, if not all, drinking water in the U.S. contains chemicals that possess mutagenic and/or carcinogenic activity by using bacterial and in vitro methods. In the present work, increased numbers of tumors were observed with samples of organic material isolated from 5 U.S. cities administered as tumor initiators in mouse skin initiation/promotion studies. Only in one case was the result significantly different from control. In studies designed to test whether disinfection practice contributes significantly to the tumor initiating activity found in drinking water mixed results have been obtained. In one experiment, water disinfected by chlorination, ozonation or combined chlorine resulted in a significantly greater number of papillomas when compared to nondisinfected water. In two subsequent experiments, where water was obtained from the Ohio River at different times of the year, no evidence of increased initiating activity was observed with any disinfectant. Analysis of water obtained at the comparable times of the year for total organic halogen, and trihalomethane formation revealed a substantial variation in the formation of these products. Considering the problems such variability poses for estimating risks associated with disinfection by-products, a model system which makes use of commercially obtained humic acid as a substrate for chlorination was investigated using the Ames test. Humic and fulvic acids obtained from two surface waters as well as the commercially obtained humic acid were without activity in TA 1535, TA 1537, TA 1538, TA 98 or TA 100 strains of S. typhimurium. Following treatment with a 0.8 molar ratio of chlorine (based on carbon) significant mutagenic activity was observed with all humic and fulvic acid samples. Comparisons of the specific mutagenic activity of the chlorinated products suggests that the commercial material might provide a useful model for studying health hazards associated with disinfection reactions by-products.

Mechanistic considerations for carcinogenic risk estimation: chloroform.

Abstract: Chloroform has been reported to induce cancer in rodents after chronic administration of high doses by gavage. However, the interpretation of these findings is hampered by a lack of knowledge concerning the relative roles of genetic and nongenetic mechanisms in these bioassays. The present studies were carried out in male B6C3F1 mice in order to investigate the potential of chloroform to induce genetic damage and/or organ toxicity at the sites where tumors have been observed in the various bioassays. These studies revealed that carcinogenic doses of chloroform produced severe necrosis at the sites where tumors later developed. This was demonstrated by light microscopy as well as by determination of the cellular regeneration index following administration of 3H-thymidine. Noncarcinogenic doses of chloroform failed to induce these responses. In contrast, studies of DNA alkylation and DNA repair in vivo failed to give any indication that chloroform had produced the type of genetic alterations associated with known genotoxic chemicals. These data suggest that the primary mechanism of chloroform-induced carcinogenesis is nongenetic in nature. If the same mechanism predominates in man, there should be little to no carcinogenic risk associated with exposure to noncytotoxic levels of chloroform.

Toxicology of organic drinking water contaminants: trichloromethane, bromodichloromethane, dibromochloromethane and tribromomethane

Abstract: This study evaluated the subchronic toxicity of selected halomethanes which are drinking water contaminants. The compounds studied were trichloromethane, bromodichloromethane, dibromochloromethane and tribromomethane. Subchronic 14-day gavage studies were performed with the use of doses encompassing one-tenth the LD50 for the compounds. A 90-day gavage study of one of the compounds, trichloromethane, was also done. Parameters observed included body and organ weights, histopathology, hematology, clinical chemistries, and hepatic microsomal enzyme activities. Toxicity to the humoral immune system was assessed by measuring the number of splenic IgM antibody-forming cells and the serum antibody level to sheep erythrocytes. Cell-mediated immunity was evaluated by measuring the delayed type hypersensitivity response and popliteal lymph node proliferation response to sheep red blood cells. The functional activity of the reticuloendothelial system, as measured by the vascular clearance rate and tissue uptake of 51Cr sheep red blood cells was also determined. The major effects of the halomethanes were increased liver weights, elevations of SGPT and SGOT, decreased spleen weights and a decrease in the number of splenic IgM antibody-forming cells. The humoral immune system appeared to be an indicator of halomethane toxicity. There is evidence that subchronic 14-day exposure may be of greater value than long-term studies in determining the toxicity of these compounds.