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Showing papers in "Environmental Health Perspectives in 1986"


Journal ArticleDOI
TL;DR: A hypothetical model is presented for the metabolism of aluminum, based on documented direct observations of Al3+ and analogies from other ions, and it is proposed that an accumulation may take place at a subcellular level without any significant increase in the corresponding tissue concentration.
Abstract: Literature regarding the biochemistry of aluminum and eight similar ions is reviewed. Close and hitherto unknown similarities were found. A hypothetical model is presented for the metabolism, based on documented direct observations of Al3+ and analogies from other ions. Main characteristics are low intestinal absorption, rapid urinary excretion, and slow tissue uptake, mostly in skeleton and reticuloendothelial cells. Intracellular Al3+ is probably first confined in the lysosomes but then slowly accumulates in the cell nucleus and chromatin. Large, long-lived cells, e.g., neurons, may be the most liable to this accumulation. In heterochromatin, Al3+ levels can be found comparable to those used in leather tannage. It is proposed that an accumulation may take place at a subcellular level without any significant increase in the corresponding tissue concentration. The possible effects of this accumulation are discussed. As Al3+ is neurotoxic, the brain metabolism is most interesting. The normal and the lethally toxic brain levels of Al3+ are well documented and differ only by a factor of 3-10. The normal brain uptake of Al3+ is estimated from data on intestinal uptake of Al3+ and brain uptake of radionuclides of similar ions administered intravenously. The uptake is very slow, 1 mg in 36 years, and is consistent with an assumption that Al3+ taken up by the brain cannot be eliminated and is therefore accumulated. The possibility that Al3+ may cause or contribute to some specific diseases, most of them related to aging, is discussed with the proposed metabolic picture in mind.

480 citations


Journal ArticleDOI
TL;DR: The influence of relative humidity on the abundance of allergens, pathogens, and noxious chemicals suggests that indoor relative humidity levels should be considered as a factor of indoor air quality.
Abstract: A review of the health effects of relative humidity in indoor environments suggests that relative humidity can affect the incidence of respiratory infections and allergies. Experimental studies on airborne-transmitted infectious bacteria and viruses have shown that the survival or infectivity of these organisms is minimized by exposure to relative humidities between 40 and 70%. Nine epidemiological studies examined the relationship between the number of respiratory infections or absenteeism and the relative humidity of the office, residence, or school. The incidence of absenteeism or respiratory infections was found to be lower among people working or living in environments with mid-range versus low or high relative humidities. The indoor size of allergenic mite and fungal populations is directly dependent upon the relative humidity. Mite populations are minimized when the relative humidity is below 50% and reach a maximum size at 80% relative humidity. Most species of fungi cannot grow unless the relative humidity exceeds 60%. Relative humidity also affects the rate of offgassing of formaldehyde from indoor building materials, the rate of formation of acids and salts from sulfur and nitrogen dioxide, and the rate of formation of ozone. The influence of relative humidity on the abundance of allergens, pathogens, and noxious chemicals suggests that indoor relative humidity levels should be considered as a factor of indoor air quality. The majority of adverse health effects caused by relative humidity would be minimized by maintaining indoor levels between 40 and 60%. This would require humidification during winter in areas with cold winter climates. Humidification should preferably use evaporative or steam humidifiers, as cool mist humidifiers can disseminate aerosols contaminated with allergens.

457 citations


Journal ArticleDOI
TL;DR: The PhIP, which contributes the highest mass content to the cooked meat, but has the lowest mutagenic potency, might ultimately make a significant contribution to the carcinogenicity.
Abstract: The purification of cooking mutagens depends on the extraordinary sensitivity of the Ames/Salmonella mutagenicity test and its usefulness for tracking the mutagens during the purification steps. Fo...

258 citations


Journal ArticleDOI
TL;DR: It is suggested that phthalate esters may act initially to cause Sertoli cell injury, the subsequent loss of germ cells occurring as a consequence of this, and that the latter may be the active testicular toxin from DEHP.
Abstract: Di(2-ethylhexyl) phthalate (DEHP) produced seminiferous tubular atrophy and reductions in seminal vesicle and prostate weight in 4-week-old, but not in 15-week-old rats. Di-n-pentyl phthalate (DPP) did produce atrophy in the older rats but this developed more slowly than in young animals. Coadministration of testosterone or gonadotrophins did not protect against phthalate-induced testicular toxicity but did partly reverse the depression of seminal vesicle and prostate weight. Secretion of seminiferous tubule fluid and androgen binding protein by the Sertoli cells was markedly suppressed within 1 hr of a dose of DPP or mono-2-ethylhexyl phthalate (MEHP) in immature rats. This occurred less rapidly in mature rats. [14C]Mono-n-pentyl phthalate and [14C]MEHP penetrated the blood testis barrier only to a very limited extent. These findings and the early morphological changes in the Sertoli cells produced by DPP suggest that phthalate esters may act initially to cause Sertoli cell injury, the subsequent loss of germ cells occurring as a consequence of this. Some features of the testicular lesion could be reproduced in primary cocultures of rat Sertoli and germ cells. Structure activity studies with a range of phthalate monoesters showed good agreement between the induction of germ cell detachment in culture and testicular toxicity in vivo. Three metabolites of MEHP (metabolites V, VI, and IX) were much less toxic in culture than MEHP itself, suggesting that the latter may be the active testicular toxin from DEHP.

203 citations


Journal ArticleDOI
TL;DR: It is concluded that the prediction of the human response based on animal studies can be improved by consideration of the appropriate pharmacokinetic determinants, and it must be investigated if peak concentrations or the area under the concentration-time curve (AUC) correlate with the teratogenic response.
Abstract: Interspecies differences in regard to the teratogenicity of drugs can be the result of differing pharmacokinetic processes that determine the crucial concentration-time relationships in the embryo. Maternal absorption, as well as distribution, of the drugs does not usually show great species differences. The first-pass effect after oral application is often more pronounced in animals than man (e.g., valproic acid, 13-cis-retinoic acid), although in some cases the reverse was found (e.g., hydrolysis of valpromide). Existing differences can be adjusted by appropriate choice of the administration route and measurements of drug levels. Many variables determine the placental transfer of drugs: developmental stage, type of placenta, properties of the drug. Even closely related drugs (e.g., retinoids) may differ greatly in regard to placental transfer. Maternal protein binding is an important determinant of placental transfer, since only the free concentration in maternal plasma can equilibrate with the embryo during organogenesis; this parameter differs greatly across species (e.g., valproic acid: five times higher free fractions in mouse and hamster than in monkey and man). The metabolic pattern has not yet been demonstrated to be a major cause of species differences, although recent evidence on phenytoin and thalidomide support the hypothesis that some species differences can be the result of differing activation/deactivation pathways. Laboratory animals usually have a much higher rate of drug elimination than man. Drastic drug level fluctuations are therefore present during teratogenicity testing in animals, but not to the same degree in human therapy. It must, therefore, be investigated if peak concentrations (such as for valproic acid and possibly caffeine) or the area under the concentration-time curve (AUC) (such as for cyclophosphamide and possibly retinoids) correlate with the teratogenic response. Only then is a rational and scientific basis for interspecies comparison possible. It is concluded that the prediction of the human response based on animal studies can be improved by consideration of the appropriate pharmacokinetic determinants.

182 citations


Journal ArticleDOI
TL;DR: This supplement includes results of 280 long-term, chronic experiments of 114 test compounds, and reports the same information about each experiment in the same plot format as the earlier publication, "A Carcinogenic Potency Database of the Standardized Results of Animal Bioassays".
Abstract: This paper is a chronological supplement to the earlier publication, A Carcinogenic Potency Database of the Standardized Results of Animal Bioassays. The authors report here results of carcinogenesis bioassays published in Technical Reports of the National Cancer Institute/National Toxicology Program between July 1980 and December 1982, and the general literature between July 1981 and December 1982. This supplement includes results of 280 long-term, chronic experiments of 114 test compounds, and reports the same information about each experiment in the same plot format as the earlier paper: e.g., the species and strain of test animal, the route and duration of compound administration, dose level and other aspects of experimental protocol, histopathology and tumor incidence, TD/sub 50/ and its statistical significance, dose response, author's opinion about carcinogenicity, and literature reference. While a number of appendices are provided to facilitate use of this supplement, the authors have not duplicated here the material published earlier. Instead, they refer the reader to the earlier publications for a thorough description of the numerical index of carcinogenic potency (TD/sub 50/), a guide to the plot of the database, and a discussion of the sources of data, the rationale for the inclusion of particular experiments and particular targetmore » sites, and the conventions adopted in summarizing the literature. For 44 of the 114 chemicals reported in this second plot, results of earlier experiments are also given in the first plot; since only 1981-1982 results are reported here, the first plot is required for these repeated compounds. In this paper they also give corrections for errors, that appeared in the earlier publication.« less

171 citations


Journal ArticleDOI
TL;DR: These studies demonstrate a marked species difference in the response of hepatocytes to MEHP-elicited peroxisome proliferation, which may be due to an initial biochemical lesion of fatty acid metabolism.
Abstract: The exposure of cultured rat hepatocytes to mono(2-ethylhexyl)phthalate (MEHP) for 72 hr resulted in marked induction of peroxisomal enzyme activity (beta-oxidation; cyanide-insensitive palmitoyl C...

169 citations


Journal ArticleDOI
TL;DR: The principles of radiobiology that can explain the time of onset, duration, and severity of the complex reactions of the lung to ionizing radiation are outlined and emphasis is placed on the data showing that alpha emitters are at least an order of magnitude more hazardous than beta/gamma radiation.
Abstract: This article outlines the principles of radiobiology that can explain the time of onset, duration, and severity of the complex reactions of the lung to ionizing radiation. These reactions have been assayed biochemically, cell kinetically, physiologically, and pathologically. Clinical and experimental data are used to describe the acute and late reactions of the lung to both external and internal radiation including pneumonitis, fibrosis and carcinogenesis. Acute radiation pneumonitis, which can be fatal, develops in both humans and animals within 6 months of exposure to doses greater than or equal to 8 Gy of low LET radiation. It is divisible into a latent period lasting up to 4 weeks; an exudative phase (3-8 weeks) and with an acute pneumonitic phase between 2 and 6 months. The latter is an inflammatory reaction with intra-alveolar and septal edema accompanied by epithelial and endothelial desquamation. The critical role of type II pneumonocytes is discussed. One favored hypothesis suggests that the primary response of the lung is an increase in microvascular permeability. The plasma proteins overwhelm the lymphatic and other drainage mechanisms and this elicits the secondary response of type II cell hyperplasia. This, in its turn, produces an excess of surfactant that ultimately causes the fall in compliance, abnormal gas exchange values, and even respiratory failure. The inflammatory early reaction may progress to chronic fibrosis. There is much evidence to suggest that pneumonitis is an epithelial reaction and some evidence to suggest that this early damage may not be predictive of late fibrosis. However, despite detailed work on collagen metabolism, the pathogenesis of radiation fibrosis remains unknown. The data on radiation-induced pulmonary cancer, both in man and experimental animals from both external and internal irradiation following the inhalation of both soluble and insoluble alpha and beta emitting radionuclides are reviewed. Emphasis is placed on the data showing that alpha emitters are at least an order of magnitude more hazardous than beta/gamma radiation and on recent data showing that the more homogeneous the irradiation of the lung, the greater is the carcinogenic hazard which contradicts the so-called "hot particle" theory.

163 citations


Journal ArticleDOI
TL;DR: Investigation of the abilities of various agents to hydroxylate deoxyguanosine or guanine base in DNA found various reducing agents, metals, asbestoses, polyphenols, aminophenols, and X-ray were effective forHydroxylation and an oxygen radical seems to be the reactive species.
Abstract: Heated glucose is mutagenic to Salmonella typhimurium TA 100 in the absence of S-9 mix. For identifying unknown mutagens in heated glucose (dry solid, 200 degrees C, 20 min), reaction with isopropylideneguanosine (IPG) was followed by isolation and characterization of the mutagen-IPG adduct. Two adducts, glyoxal-IPG and 8-hydroxy-IPG, were identified in the reaction mixture by this technique. To elucidate the mechanism of this hydroxylation reaction, we investigated the abilities of various agents to hydroxylate deoxyguanosine or guanine base in DNA. Various reducing agents, metals, asbestoses, polyphenols, aminophenols, and X-ray were effective for hydroxylation, and an oxygen radical seems to be the reactive species. For sensitive detection of 8-hydroxyguanine, a monoclonal antibody for it was prepared.

149 citations


Journal ArticleDOI
TL;DR: The reaction products of ozone that form during the oxidation of compounds found in aqueous media are reviewed and more research is required before a valid assessment of the risks of ozone by-products can be made.
Abstract: The reaction products of ozone that form during the oxidation of compounds found in aqueous media are reviewed. Reaction products of ozone are well documented only for a limited number of substrates, and mechanistic information is quite rare. Decomposition of ozone during its reactions, sometimes induced by matrix impurities or by the by-products of the reactions, will generate highly reactive hydroxyl radicals. Thus, even reactions occurring at pH less than 7 may have radical character. More complete destruction of organic substrates may be enhanced by using catalysts, such as ultraviolet radiation or hydrogen peroxide, to accelerate radical formation. However, complete mineralization is generally not practical economically, so partially oxidized by-products can be expected under typical treatment conditions. Ozone by-products tend to be oxygenated compounds that are usually, but not always, more biodegradable and less toxic than xenobiotic precursors. Of particular interest are hydroperoxide by-products, which may have escaped detection because of their lability, and unsaturated aldehydes. Inorganic by-products tend to be in high oxidation states, which in some cases (e.g., some metallic elements) may lead to enhanced removal by flocculation and sedimentation. In other cases oxidation may lead to formation of reactive species such as hypobromous acid from bromide ion or permanganate from manganous ion. In general, more research is required before a valid assessment of the risks of ozone by-products can be made.

146 citations


Journal ArticleDOI
TL;DR: Sperm from ejaculated semen or the cauda epididymidis can be evaluated for normalcy of morphology or function and should be used for artificial insemination of females to critically evaluate fertility, and among the more sensitive criteria of testicular function are the minor diameter of essentially round seminiferous tubules, the ratio of leptotene spermatocytes to Sertoli cells, and the number of homogenization-resistant sperMatids per testis.
Abstract: The potential impact of an agent altering male reproductive function is greater for humans than for animals. Consequently, it is essential that sensitive criteria be used to look for effects on a multiplicity of target sites when an agent is evaluated using an animal model. No animal model has reproductive characteristics similar to those of humans, but this does not negate the validity of using animal models. Classic methodologies for reproductive toxicology are limited by the approaches used for subjective evaluation of testicular histology and use of natural mating for fertility tests. After dosing for an interval at least equal to six times the duration of one cycle of the seminiferous epithelium, sperm from ejaculated semen or the cauda epididymidis can be evaluated for normalcy of morphology or function and should be used for artificial insemination of females to critically evaluate fertility. Normal males of animal models ejaculate a great excess of sperm. A 50 or 90% reduction in the number of fertile sperm deposited during mating probably will not markedly reduce fertility. Artificial insemination of a critical number of sperm, selected to result in slightly less than maximal fertility for control animals, will maximize the probability of detecting a decrease in fertility if the same critical number of sperm is inseminated for treated animals as for control animals. Testicular function should be evaluated by objective, rather than subjective, criteria. For each male, a piece of testicular tissue should be appropriately fixed and an aliquot of parenchyma should be homogenized to allow enumeration of homogenization-resistant spermatids. Among the more sensitive criteria of testicular function are the minor diameter of essentially round seminiferous tubules, the ratio of leptotene spermatocytes to Sertoli cells, the corrected numbers of germ cells per seminiferous tubule cross section, and the number of homogenization-resistant spermatids per testis.

Journal ArticleDOI
TL;DR: The effects, over periods from 3 days to 9 months of administration, of diets containing di-2-ethylhexyl phthalate are very similar to those observed in rats administered diets containing hypolipidemic drugs such as clofibrate.
Abstract: The effects, over periods from 3 days to 9 months of administration, of diets containing di-2-ethylhexyl phthalate are very similar to those observed in rats administered diets containing hypolipidemic drugs such as clofibrate. Changes occur in a characteristic order commencing with alterations in the distribution of lipid within the liver, quickly followed by proliferation of hepatic peroxisomes and induction of the specialized P-450 isoenzyme(s) catalyzing omega oxidation of fatty acids. There follows a phase of mild liver damage indicated by induction of glucose-6-phosphatase activity and a loss of glycogen, eventually leading to the formation of enlarged lysosomes through autophagy and the accumulation of lipofuscin. Associated changes are found in the kidney and thyroid. The renal changes are limited to the proximal convoluted tubules and are generally similar to changes found in the liver. The effects on the thyroid are more marked. Although the levels of thyroxine in plasma fail to about half normal values, serum triiodothyronine remains close to normal values while the appearance of the thyroid varies, very marked hyperactivity being noted 7 days after commencement of treatment, this is less marked at 14 days, but even after 9 months treatment there is clear cut evidence for hyperactivity with colloid changes which indicate this has persisted for some time. Straight chain analogs of di-2-ethylhexyl phthalate, di-n-hexyl phthalate and di-n-oxtyl phthalate differ entirely in their short-term effects on the liver and kidney but have similar effects on the thyroid. The short-term in vivo hepatic effects of the three phthalate esters can be reproduced in hepatocytes in tissue culture. All three phthalate esters, as well as clofibrate, have early marked effects on the metabolism of fatty acids in isolated hepatocytes. The nature of these changes is such as to increase storage of lipid in the liver. A hypothesis is presented to explain the progress from these initial metabolic effects to the final formation of liver tumors.

Journal ArticleDOI
TL;DR: The pharmacokinetic differences between these two species indicate that the tissues of the marmoset are exposed to a level of DEHP metabolites equivalent to the complete absorption of a dose of Ca.
Abstract: Certain phthalate esters and hypolipidemic agents are known to induce morphological and biochemical changes in the liver of rodents, which have been associated with an increased incidence of hepatocellular tumors in these species. There is evidence that hypolipidemic agents do not induce these effects in either subhuman primates or man. The oral and intraperitoneal administration of di(2-ethylhexyl) phthalate (DEHP) to the marmoset monkey at doses up to 5 mmole DEHP/kg body weight/day for 14 days did not induce morphological or biochemical changes in the liver or testis comparable with those obtained in rats given the same amount of DEHP. In the marmoset, the excretion profile of [14C]-DEHP following oral, IP, and IV administration and the lower tissue levels of radioactivity demonstrated a considerably reduced absorption in this species compared to the rat. The urinary metabolite pattern in the marmoset was in many respects qualitatively similar to but quantitatively different from that in the rat; the marmoset excreted principally conjugated metabolites derived from omega- 1 oxidation. The pharmacokinetic differences between these two species indicate that the tissues of the marmoset are exposed to a level of DEHP metabolites equivalent to the complete absorption of a dose of Ca. 0.1 to 0.25 mmole DEHP/kg body weight/day without significant toxicological effects. These exposure levels are at least 100-fold greater than the worst estimates of incidental human exposure (ca. 0.0015 mmole/kg/day). They are comparable with the human therapeutic dose of many hypolipidemic drugs (ca. 0.15 mmole/kg/day), a dose at which it is claimed that there is an absence of morphological or biochemical changes to human or subhuman primate liver.(ABSTRACT TRUNCATED AT 250 WORDS)

Journal ArticleDOI
TL;DR: Although NaClO2 was shown to be noncarcinogenic in rats, the results for mice were evaluated as inconclusive and the necessity for further testing of oxidant chemicals to determine potential carcinogenic and/or promoting effects is suggested.
Abstract: Long-term in vivo carcinogenicity tests of potassium bromate (KBrO3), sodium hypochlorite (NaClO), and sodium chlorite (NaClO2) have been conducted in Japan from 1977 to 1985. In these investigations, groups of approximately 50 male and 50 female F344 rats or B6C3F1 mice were given solutions of the compounds as their drinking water ad libitum at two dose levels determined on the basis of preliminary 13-week tests. Control animals were given distilled water. The carcinogenic potential of KBrO3 was tested by administering doses of 500 or 250 ppm to rats for 110 weeks. Significantly elevated incidences of renal cell tumors in males and females and mesotheliomas of the peritoneum in males as compared to controls were observed. When female mice were given KBrO3 at doses of 1000 or 500 ppm for 78 weeks, no significant differences in tumor incidences between experimental and control groups were apparent. NaClO was administered to male and female rats, respectively, at doses of 1000 or 500 ppm and 2000 or 1000 ppm for 104 weeks. In mice, NaClO was given at doses of 1000 or 500 ppm to either sex for 103 weeks. The incidences of tumors in NaClO-treated and control animals of both sexes were not significantly different in both rat and mouse studies. NaClO2 was given to rats of both sexes at a dose of 600 or 300 ppm for 85 weeks. No statistically significant differences were observed in the incidences of tumor formation between NaClO2-treated and control groups of both sexes. NaClO2 was administered to mice at a concentration of 500 or 250 ppm for 85 weeks. In males, the combined incidences of hyperplastic nodules and hepatocellular carcinomas of the liver in a low-dose group, and adenomas and adenocarcinomas of the lung in a high-dose group, were marginally increased compared to controls (p less than 0.05). However, these incidences in treated males were within the range of values of historical control data in our program. We concluded that KBrO3 was carcinogenic in rats of both sexes. NaClO was not carcinogenic in either rats and or mice under the conditions of the present studies. Although NaClO2 was shown to be noncarcinogenic in rats, the results for mice were evaluated as inconclusive. Also the results of two-stage mouse skin carcinogenesis using KBrO3, NaClO, and NaClO2 are presented. The necessity for further testing of oxidant chemicals to determine potential carcinogenic and/or promoting effects is suggested in view of the recently proposed role of active oxygen species in carcinogenesis.

Journal ArticleDOI
TL;DR: A cup of coffee contains mutagens which produce about 5 X 10(4)-10(5) revertants of Salmonella typhimurium TA 100 without S9 mix, and one of them was identified to be methylglyoxal, which induced tumors in rats when administered by subcutaneous injection.
Abstract: A cup of coffee contains mutagens which produce about 5 X 10(4)-10(5) revertants of Salmonella typhimurium TA 100 without S9 mix. One of the mutagens was identified to be methylglyoxal. Methylglyoxal was present in various beverages such as black tea, whisky, and brandy. Methylglyoxal itself induced tumors in rats when administered by subcutaneous injection. However, the mutagenic properties of coffee were different from those of methylglyoxal. The mutagenicity of coffee was suppressed by catalase, and coffee was found to contain hydrogen peroxide. Furthermore, coffee solution was found to have a hydrogen peroxide-generating system. Instant coffee (15 mg/mL) contains 130 microM hydrogen peroxide immediately after the dissolution of coffee powder in water at room temperature. The concentration of hydrogen peroxide increased with time. The mutagenicity of methylglyoxal was increased by the copresence of hydrogen peroxide. A maximum of 30-fold enhancement was observed. The mutagenicity of black tea but not that of whisky was suppressed by catalase.

Journal ArticleDOI
TL;DR: The carcinogenic effects of di(2-ethylhexyl) phthalate (DEHP), including its potential as an initiator and as a promoter of carcinogenesis, were studied in mouse liver and skin and in rat liver in vivo, and in mouse epidermis-derived JB6 cells in vitro.
Abstract: The carcinogenic effects of di(2-ethylhexyl) phthalate (DEHP), including its potential as an initiator and as a promoter of carcinogenesis, were studied in mouse liver and skin and in rat liver in ...

Journal ArticleDOI
TL;DR: A series of mutagenic heterocyclic amines has been isolated and identified in broiled fish and meat and in pyrolyzates of amino acids and proteins, and feeding experiments showed these mutagens to be carcinogenic in mice and rats.
Abstract: Mutation assay with Salmonella typhimurium enabled us to detect various types of mutagens in cooked foods. A series of mutagenic heterocyclic amines has been isolated and identified in broiled fish...

Journal ArticleDOI
TL;DR: A lack of reproductive dysfunction in F344 male rats at DEHP doses below 20,000 ppm is suggested which produced measurable testicular degeneration and afflicted epididymal sperm morphology under the present experimental conditions.
Abstract: Dietary exposure of adult male F344 rats to 0, 320, 1250, 5000, or 20,000 ppm DEHP for 60 consecutive days resulted in a dose-dependent reduction in total body, testis, epididymis, and prostate wei...

Journal ArticleDOI
TL;DR: In this paper, an alternative approach which uses existing literature data and analytical results to calculate the "2,3,7,8-TCDD equivalent" concentration of a mixture in order to "predict" its biological potency relative to TCDD itself is presented.
Abstract: Sufficient toxicological data are now available to permit use of conventional risk assessment techniques to estimate the hazards associated with human exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD). However, many real-world exposures involve complex mixtures of dibenzodioxins, dibenzofurans, and related compounds. Historical approaches to risk assessment on such mixtures have ranged from ignoring all compounds except 2,3,7,8-TCDD itself to assuming that all compounds have potencies equal to 2,3,7,8-TCDD. An alternative approach which uses existing literature data and analytical results to calculate the "2,3,7,8-TCDD equivalent" concentration of a mixture in order to "predict" its biological potency relative to 2,3,7,8-TCDD itself is advanced here. Previously reported in vivo acute and subchronic studies and some recently obtained analytical chemistry data are integrated here to clarify the utility of this important approach and to assess the uncertainties associated with its use. This predictive approach, and various conceptually similar ones, have now found wide applicability to the risk assessment process associated with exposure to complex mixtures of dioxins, dibenzofurans, and related compounds.

Journal ArticleDOI
TL;DR: Interim data by week 83 show that MeIQ also induces forestomach tumors in addition to liver tumors, andcinogenicity tests on MeIQ are ongoing, and interim data shows that Me IQ also induces Forestomach tumor induced by Trp-P-1, Glu-P2, and IQ.
Abstract: Carcinogenicities of mutagenic heterocyclic amines in cooked foods have been tested in CDF1 mice and F344 rats of both sexes Eight heterocyclic amines--Trp-P-1, Trp-P-2, Glu-P-1, Glu-P-2, MeA alph

Journal ArticleDOI
TL;DR: One amide, feruperine, has antioxidant activity as high as the synthetic antioxidants, butylated hydroxyanisole (BHA) andbutylated hydroxytoluene (BHT) and may surpass BHA and BHT in their ability to inactivate mutagens in food.
Abstract: In a structure analysis of the compounds of the genus Piper (Family Piperaceae), we identified five phenolic amides from Piper nigrum, seven compounds from P. retrofractum, and two compounds from P. baccatum. All the phenolic amides possess significant antioxidant activities that are more effective than the naturally occurring antioxidant, alpha-tocopherol. One amide, feruperine, has antioxidant activity as high as the synthetic antioxidants, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT). Naturally occurring antioxidants, therefore, may surpass BHA and BHT in their ability to inactivate mutagens in food.

Journal ArticleDOI
TL;DR: A metabolic pathway for phthalates having saturated alkyl groups has been postulated based on identification of metabolites produced in vivo and excreted in urine, and some details of the nature of these early steps have been learned.
Abstract: There is convincing evidence in the literature that most of the adverse biological effects of phthalate diesters are actually effects of metabolites rather than of the parent compounds. If so, the dramatic species differences in endpoint metabolic profiles make it essential that metabolism of phthalates be understood in detail, including the factors that may alter the metabolism. A metabolic pathway for phthalates having saturated alkyl groups has been postulated based on identification of metabolites produced in vivo and excreted in urine. The first few steps in the postulated pathway have been confirmed in vitro using enzymatically active preparations from rats and mice; some details of the nature of these early steps have been learned. Although some information concerning later steps is available, much remains to be learned in this area. Species differences are postulated to involve kinetics of several biochemical and physiological events acting in concert or competition. Among these interacting factors are competition of at least three enzymes for phthalate monoesters as substrate, relative kidney clearance rates for different metabolites, relative Km values of oxidative enzymes for the same precursors in different species, and relative equilibria between glucuronide formation and hydrolysis. Essential information that must be obtained in the future includes which metabolites play a causal role in which biological effects, and what factors (age, diet, state of health, etc.) can modify the metabolism of phthalate esters and in what way.

Journal ArticleDOI
TL;DR: Of the factors causing enhanced disinfection resistance, protection by association with particulate matter is the most significant, and removal of particulate Matter is an important step in increasing the effectiveness of disinfection processes.
Abstract: Drinking water disinfection provides the final barrier to transmission of a wide variety of potentially waterborne infectious agents including pathogenic bacteria, viruses, and protozoa. These agents differ greatly in their innate resistance to inactivation by disinfectants, ranging from extremely sensitive bacteria to highly resistant protozoan cysts. The close similarity between microorganism inactivation rates and the kinetics of chemical reactions has long been recognized. Ideally, under carefully controlled conditions, microorganism inactivation rates simulate first-order chemical reaction rates, making it possible to predict the effectiveness of disinfection under specific conditions. In practice, changes in relative resistance and deviations from first-order kinetics are caused by a number of factors, including microbial growth conditions, aggregation, and association with particulate materials. The net effect of all these factors is a reduction in the effectiveness and predictability of disinfection processes. To ensure effective pathogen control, disinfectant concentrations and contact times greater than experimentally determined values may be required. Of the factors causing enhanced disinfection resistance, protection by association with particulate matter is the most significant. Therefore, removal of particulate matter is an important step in increasing the effectiveness of disinfection processes.

Journal ArticleDOI
TL;DR: Overall, these studies indicate that, in the case of nitrofen, the mode of teratogenic activity is uniquely different from the modes of adult toxicity.
Abstract: Nitrofen (2,4-dichloro-4'-nitrodiphenyl ether) is an herbicide with potent teratogenic activity in rats. When administered at doses as low as 0.15 mg/kg/day during organogenesis, abnormal development of the heart, kidneys, diaphragm, and lung occurs. The specific pattern of visceral malformations produced in the absence of overt maternal toxicity or embryolethality/cytotoxicity suggest that the compound perturbs processes unique or highly selective for embryonic differentiation. Despite findings of metabolic activation to mutagenic intermediates and carcinogenic activity in adult rodents, several lines of evidence indicate that teratogenicity is not based on mutagenic insult to the embryo. Rather, evidence is accumulating that nitrofen exerts a teratogenic effect via alterations in thyroid hormone status. The premature and pharmacologic exposure of the embryo to a nitrofen-derived thyromimetic challenge is believed to be the cause of abnormal morphogenesis of the heart, lungs, kidneys, and diaphragm. The parent compound itself could directly bind to embryonic nuclear receptors for T3, leading to altered differentiation of target organs. Alternatively, increased availability and placental transport of free thyroid hormones in the maternal compartment could be the source of thyromimetic challenge to the embryo. Overall, these studies indicate that, in the case of nitrofen, the mode of teratogenic activity is uniquely different from the mode of adult toxicity.

Journal ArticleDOI
TL;DR: The SENCAR mouse model provides a good dose-response relationship for many carcinogens used as tumor initiators and for many compounds used as tumors promoter, and has one of the largest data bases for carcinogens and promoters.
Abstract: The SENCAR mouse stock was selectively bred for eight generations for sensitivity to skin tumor induction by the two-stage tumorigenesis protocol using 7,12-dimethylbenz(a)anthracene (DMBA) as the initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as the promoter. The SENCAR mouse was derived by crossing Charles River CD-1 mice with skin-tumor-sensitive mice (STS). The SENCAR mice are much more sensitive to both DMBA tumor initiation and TPA tumor promotion than CD-1, BALB/c, and DBA/2 mice. An even greater difference in the sensitivity to two-stage skin tumorigenesis is apparent between SENCAR and C57BL/6 mice when using DMBA-TPA treatment. However, the SENCAR and C57BL/6 mice have a similar tumor response to DMBA-benzoyl peroxide treatment, suggesting that TPA is not an effective promoter in C57BL/6 mice. The DBA/2 mice respond in a similar manner to the SENCAR mice when using N-methyl-N-nitro-N-nitrosoguanidine (MNNG)-TPA treatment. The SENCAR mouse model provides a good dose-response relationship for many carcinogens used as tumor initiators and for many compounds used as tumor promoter. When compared to other stocks and strains of mice, the SENCAR mouse has one of the largest data bases for carcinogens and promoters.

Journal ArticleDOI
TL;DR: It is concluded that in assessing risks of testicular injuries in children exposed to DEHP, additional studies are required using species in which testicular development is more similar to that of humans.
Abstract: Spermatogenesis starts soon after birth in the Sprague-Dawley rat but is not fully established until about 56 days of age. When high oral doses of the plasticizer di(2-ethylhexyl) phthalate (DEHP) ...

Journal ArticleDOI
TL;DR: Results from these tests indicate that chlorinated isocyanurates are safe for use in swimming pools, and findings from acute, subchronic, reproduction, metabolism, mutagenicity, and chronic/carcinogenicity tests on cyanurate are summarized.
Abstract: Chlorinated cyanurates are added to swimming pools as disinfectants. In the presence of water, these materials hydrolyze to yield cyanurate and hypochlorous acid. To evaluate the safety of exposure to these materials, a comprehensive testing program was undertaken. This review summarizes the results of acute and subchronic tests on chlorinated isocyanurates. Findings from acute, subchronic, reproduction, metabolism, mutagenicity, and chronic/carcinogenicity tests on cyanurate are also summarized. Results from these tests indicate that chlorinated isocyanurates are safe for use in swimming pools.

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TL;DR: Until evidence is presented that substantially lowers the known body burden of methylmercury which causes toxicity, calculations indicate that the current 1.0 ppm regulatory level provides adequate protection for the average fish consumer, for young children, and for a significant number of consumers exceeding the acceptable daily intake.
Abstract: The dangers associated with the consumption of large amounts of methylmercury in fish are well recognized, and there is some evidence to suggest that methylmercury may be the cause of subtle neurological impairments when ingested at even low to moderate levels, particularly the prenatal and early childhood periods. This concern has prompted a continuing assessment of the risk of methylmercury toxicity among fish consumers in the United States as well as other countries. The toxicokinetics of methylmercury in humans are reviewed and used to estimate body burdens associated with toxic effects. To determine seafood consumption patterns among the continental U.S. population the Food and Drug Administration (FDA) has analyzed data from a diary study commissioned by the Tuna Research Foundation. Mercury residue levels in domestic fish sampled by the FDA were used to determine the level of exposure to methylmercury. Until evidence is presented that substantially lowers the known body burden of methylmercury which causes toxicity, calculations indicate that the current 1.0 ppm regulatory level provides adequate protection for the average fish consumer, for young children, and for a significant number of consumers exceeding the acceptable daily intake. However, additional studies are being carried out in a continuing process to ensure that safe levels of prenatal exposure to mercury residues in fish are maintained.

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TL;DR: The mucociliary clearance system is a first line of defense against inhaled agents, and so its compromise can adversely affect health, presenting the view that for low level exposures, changes in secretions are probably responsible for most observed changes in clearance.
Abstract: The mucociliary clearance system is a first line of defense against inhaled agents, and so its compromise can adversely affect health. The purpose of this paper is to provide a review of data on the effect of in vivo air pollutant exposures on the clearance of test particles from airways. Data from both animals and humans are compared whenever possible, so that estimates of human health effects may be made. Mechanisms of action are also discussed, presenting the view that for low level exposures, changes in secretions are probably responsible for most observed changes in clearance. The pollutants pertinent to this review are those that are common in the environment and most likely to have impacts on large numbers of people: sulfur oxides, sulfuric acid mist, O3, NO2, particulates, diesel exhaust, and cigarette smoke.

Journal ArticleDOI
TL;DR: Comparative morphometric and biochemical data from rats treated with varying dose levels of ciprofibrate, a hypolipidemic drug, and di(2-ethylhexyl) phthalate, and the widely used plasticizers, indicate that the hepatocarcinogenic potency of these agents is correlatable with their ability to induce peroxisome proliferation,peroxisomal beta-oxidation and PPA-80.
Abstract: Peroxisome proliferation is inducible in hepatocytes of rodent and nonrodent species by structurally dissimilar hypolipidemic drugs and certain phthalate ester plasticizers. The induction of peroxisome proliferation appears to be a tissue specific response limited largely to the hepatocyte. Peroxisome proliferation is associated with increases in the activity of the H2O2-generating peroxisomal fatty acid beta-oxidation system and in the amount of peroxisome proliferation-associated 80,000 MW polypeptide (PPA-80). Chronic administration of these non-DNA damaging and nonmutagenic peroxisome proliferators to rats and mice results in the development of hepatocellular carcinomas. Comparative morphometric and biochemical data from rats treated with varying dose levels of ciprofibrate, a hypolipidemic drug, and di(2-ethylhexyl) phthalate, and di(2-ethylhexyl) adipate, the widely used plasticizers, indicate that the hepatocarcinogenic potency of these agents is correlatable with their ability to induce peroxisome proliferation, peroxisomal beta-oxidation and PPA-80. Available evidence strongly favors the role of peroxisome proliferation-associated oxidative stress in the induction of liver tumors by peroxisome proliferators.