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doi: 10.1177/074823378900500503pmid: 2683218
The greatest challenge facing human populations today is that of extraordinary rapid change. Such a change in the society is illus trated by the increasing public awareness of environmental issues, accompanied by continuously expanding scientific investigations of chemical pollution. Our industrial civilization has developed and introduced into the various environmental media many compounds affecting human health individually and as a society. The science of toxicology is the evaluation of the effects of chemical and physical agents in various biological systems. Most chemical compounds cannot be tested in man due to their possible carcinogenic, muta genic, teratogenic, or other long-term toxic potential. Therefore, carefully designed toxicologic studies in other species, especially mammalian, are conducted to provide biological dose-response data, which can be used to predict human response. Toxicologists have the responsibility of providing accurate scientific dose- response data based on experiments employing, among others, "practical" concentrations of pollutants or toxicants. When the toxic effects are considered, the action of these agents in the atmosphere, water, and other environmental vehicles should be considered. There are always interacting events that co-exist in the environment. Multiple causality as a factor of a disease is well established but frequently overlooked. The various issues in envi ronmental health need to be tied together in order to be understood by scientists who are not intimately familiar with risk assessment procedures as they relate to the implementation of environmental laws. Much effort is needed both in the area of improved risk assessment methodology as well as in the area of toxicologic testing and validation of the theoretical approaches. The U.S. EPA is making every reasonable effort to improve its risk assessment approach.
doi: 10.1177/074823378900500504pmid: N/A
Daniel, F. Bernard ;Chang, Lina W. ;Schenck, Kathleen M. ;Deangelo, Anthony B. ;Skelly, Michael F.
doi: 10.1177/074823378900500506pmid: 2815100
Recently, we have detailed a DNA alkaline unwinding assay (DA UA) that can be used to rapidly measure chemically induced strand breaks in mammalian cells (Daniel et al., 1985). In this paper we present further development of this assay, including: (1) studies on the relationship between DNA adducts and DNA strand breaks; (2) evaluation of the role of cytotoxicity in DNA strand breaks; and (3) application of the DA UA to cell preparations from the liver of mice dosed with methylating agents. The level of DNA adducts produced in human CCRF-CEM cells by treatment with benzo(a)pyrene diol-epoxide (BPDE), N-acetoxy-2-acetyl amino fluorene (AAAF), and various methylating agents was linear with concentration over several orders of magnitude. Likewise, the level of strand breaks increased with the concentration over the same dose range. The strand breaks/adduct ratio ranged from 0.05 for the methyl adducts to 0.001 for the BPDE adducts. Using these values and the inherent sensitivity of the DA UA (circa 100 to 1000 breaks/ cell), (Daniel et al., 1985), the ability of the assay to detect DNA damage induced by various classes of chemical carcinogens can be calculated. The DA UA appears to be useful for assessing the relative potency of various environmental genotoxic effects on mammalian cells. In addition, it can be conducted on cells isolated from target organs of whole animals.
doi: 10.1177/074823378900500507pmid: 2683220
Kinetic interactions among chemicals present in a mixture can influence the relationship between administered and delivered or effective dose; these interactions are distinct from dynamic interac tions such as, for example, competition between two chemicals for receptor binding sites. The relationship between administered and effective dose depends on a number of biochemical, physiological, and physical factors such as age, sex, level of physical activity, route of administration, dose pattern, and bioavailability. In addi tion, interactions among chemicals may limit or increase the effec tive dose relative to the administered dose for any of the chemicals of a mixture. If the mechanism of the interaction is known, the direction and general magnitude of its effects may be predictable. A variety of potential interactions is briefly reviewed, and selected illustrations of these interactions are given. Two types of interac tions likely to be pervasive in mixtures of chemically related bioac tive materials are considered in greater detail. These interactions are induction of metabolizing enzymes such as the mixed-function oxidases, and competition of structurally similar chemicals for active sites on metabolizing enzymes. Simulations are presented to illustrate the consequences of these interactions, and examples of their occurrence are given.
Kostial, Krista ;Blanu, Maja ;Maljkovi, Teodora ;Kello, Dinko ;Rabar, Ivan ;Stara, Jerry F.
doi: 10.1177/074823378900500509pmid: 2815101
The purpose of this work was to determine whether a metal mix ture added to diet influences the toxicokinetics and toxicity of some elements. The metal mixture (MM) used in these experiments was ash (slag) from a coal gasification plant. The effect of this mixture (5 percent in diet) on the toxicokinetic and on the acute or subchronic toxicity of Cd, Hg, Mn was determined in rats of different ages. Rats were exposed for five weeks in toxicokinetic and six weeks in acute tox icity experiments. Sucklings were exposed through their mothers, which received the MM in diet over the pregnancy and lactation period. In toxicokinetic studies, half of the animals additionally received Cd, Hg or Mn (100, 50 or 2000 ppm, respectively) in drinking water. In subchronic experiments, six-week-old albino rats of both sexes were given MM in the diet and Cd, Hg or Mn in drinking water for 16 weeks. In toxicokinetic studies, 115mCd,203Hg or 54Mn were administered orally or intraperitoneally to mothers and pups. Exposure to MM had no effect on the absorption, retention and organ distribution of these elements determined six days after radioisotope administra tion. In acute toxicity studies, exposure to MM in diet had no effect on LD50values obtained eight days after oral administration of Cd, Hg or Mn to rats of different ages. In subchronic experi ments, the effect of individual metals (Cd, Hg or Mn) was similar in animals with and without simultaneous exposure to the metal mixture (only a slight potentiation of a few health-effect parameters of cadmium was noticed in some animals). It is concluded that oral exposure to MM in the diet had almost no effect on the toxicokinetics and toxicity of Cd, Hg and Mn. This could be explained by the low level or low bioavailability of ele ments from MM, by the metal-metal interaction within the mixture or by the choice of health effect indicators determined. These results are presented as one of the potential approaches for study ing the health effect of a metal mixture as occurring in the environment.
Soffritti, Morando ;Maltoni, Cesare ;Maffei, Francesca ;Biagi, Roberta
doi: 10.1177/074823378900500510pmid: 2815102
Male and female Sprague-Dawley rats of different ages at the start of the experiments (12 day embryos, and 7 and 25 weeks old) were administered formaldehyde in drinking water at different doses (2,500 or 1,500, 1,000, 500, 100, 50, 10, 0 ppm). An increased incidence of leukemias and of gastro-intestinal tu mors was observed in formaldehyde treated rats. Gastro-intestinal tumors are exceptionally rare in the rats of the colony used. These results, together with the ones obtained by other Authors on rats exposed by inhalation to formaldehyde, indicate that this compound is an experimental multipotential carcinogen. The experimental results presented in this report give scientific support to the epidemiological observation of a higher incidence of leukemias and of gastro-intestinal cancers among the people occu pationally exposed.
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