Effects on Laboratory Animals

Many experimental obs vations, some of which have predicted human cancer data, have been possible because of organ-specific animal models for chemical carcinogenesis. These models, being similar to thdr human counterparts, strengthen the association of environmental exposures with cancer development, and aid in the extrapolation of carcinogenesis data from animal species to humans. They also provide a valuable resource for studies of pathogenesis, risk-modifying factors, and cancer prevention. 

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Sources of Information. The toxic properties of the major E P were reviewed in several technical reports of the early 1970 s TNT (Refs 14 33), RDX/HMX (Ref 12), NC (Ref 14), NG (Ref 14), Tetranitromethane (Ref 18) and Methyl nitrate (Ref 18). Recent exptl studies cited below provide important additional data, especially on the chronic effects on laboratory animals... 

The following pages provide brief information on a few selected solvents, including the manner of exposure and toxicological effects on laboratory animals and on humans. For purposes of easy and quick identification and reference by the nser, the solvents are listed in alphabetical order rather than according to the chemical classes to which they belong. The chemical class of each solvent may be fonnd in Appendix 4.1. For more detail on each of the chemical substances, refer to the literature. ... 

The dangerous acute dose of the technical mixture has been estimated at about 30 g and the dangerous dose of lindane at about 7 to 15 g. However, as already mentioned, a single dose of 45 mg (or approximately 0.65 mg/kgD of lindane caused convulsions. Lindane shows a marked difference in toxicity to different species. Its toxic effect on laboratory animals compares favorably with that of DDT, but for several domestic animals, notably calves, lindane is more toxic than DDT or dieldrin. On a chronic systemic basis the a, p and y isomers are experimental carcinogens. Has been implicated in aplastic anemia. 

Harada et al. (148) reported that no significant pharmacological activities were observed for the four synthetic stereoisomers possible for ( )-C-noremetine Pyman [( )-176]. An aqueous (boiled) extract of A. chinense (Lour.) Harms, containing ( )-anabasine (69) as the single active component, was tested for its muscle relaxation effects on laboratory animals and clinical cases (405). A fraction of the CHCI3 extract of A. chinense was found... 

Rose oil when added to the food has been reported to have choleretic effects on cats. Bulgarian rose oil has been reported to decrease urinary corticosteroids and serum ceruloplasmin, as well as elicit other effects on laboratory animals when administered intraperitoneally or intravenously. ... 

There are several protopine-type alkaloids including protopine (7), cryptopine, a-allocryptopine and 13-oxocryptopine. These alkaloids are of Uttle importance and have no analgaesic activity. Protopine does have a sedative effect on laboratory animals. 

W. J. Hayes, Jr., and E. R. Laws, Jr., eds.. Handbook of Pesticide Toxicology, Academic Press, Inc., San Diego, Calif., 1990. Three volume set provides detailed toxicological profiles of more than 250 insecticides, herbicides, and fungicides each compound described by identity, properties, and uses toxicity to humans, laboratory animals, domestic animals, and wildlife includes comprehensive coverage of diagnosis, treatment, prevention of injury, effects on domestic animals, wildlife, and humans - ISjOOO references. 

In the laboratory the chemical was put into water at the ordinary spray dilution of 1 to 800 and after 24 hours standing the treated water was used as drinking water for test animals. There were no reactions, evidence of poison, or undesirable effects on any animals as a result of these tests, even with long feeding periods. It was not possible to differentiate between test animals and check animals by any of the customary tests. 

With respect to veterinary medicines, the US-FDA establishes tolerances to include a safety factor to assure that the drug will have no harmful effects on consumers of the food product. The US-FDA first determines the level at which the dmg does not produce any measurable effect in laboratory animals. From this, the US-FDA determines an acceptable daily intake (ADI), and the drug tolerance and withdrawal times are then determined so that the concentrations of dmg residues in edible tissues are below the ADI. Depending on the dmg, safety factors of between 100-fold to 2000-fold are included in the calculations used to set the tolerances. 

Pharmacologists evaluate the effects of the drug on laboratory animals in shortterm and long-term studies. 

Hepatic Effects. No information is available on the hepatic effects of HDI in humans. Limited information exists on these effects in laboratory animals and is confined to inhalation studies. One study of intermediate-duration showed decreased liver weights in female rats dosed at 0.3 ppm (Mobay Corporation 1984) however, 2 studies of longer durations and slightly lower inhaled doses showed no ehanges in liver weights attributable to HDI toxieity (Mobay Corporation 1988, 1989). It appears that the ehanges in liver weights are a transitory phenomenon in laboratory animals. 

Acute, Intermediate and Chronic-Duration Exposures. Inhalation exposures in both humans and laboratory animals predominate in the available information on acute, intermediate, and chronic effects of HDl, and will be considered here as a group. Information on laboratory animals describes the direct irritant effects of HDl, which was usually inhaled in large doses (>4 ppm) however, no information on the allergic component of HDl toxicity at low doses, the type of dose most commonly encountered in humans, was provided. Information on acute inhalation exposure of humans may be misleading. In most cases of acute exposure, the workers had been exposed to HDl and HDl prepolymers in their workplace for several months or several years (doses often not available). These workers were then tested with a small dose of either HDl or a product containing HDl with the HDl prepolymers and other organics. 

In addition, while hundreds of chemicals have been found to cause carcinogenic effects in laboratory animals, definite evidence of human cardnogenidty exists for only a score or more (lARC, 1982). At present, therefore, estimates of the cardnogenidty of most chemicals for man must be based largely on tests in laboratory animals, supported by andllaiy data from other types of bioassays and from knowledge of the relationship between molecular structure and biological activity. 

Environmental transport, distribution and transformation Environmental levels and human exposure Kinetics and metabolism in laboratory animals and humans Effects on laboratory mammals and in vitro test systems Effects on humans... 

The hazard assessment identifies the adverse effects that a chemical may cause and investigates the relationship between their magnitude and the dose to which an organism is exposed. A major source of uncertainty is the use of data from tests on laboratory animals (or plants) to investigate toxicity to other species (including humans). There are at least four reasons why there is uncertainty in the application of test data to exposures of humans and wild animals (RCEP, 2003, pp21—22 Rodricks, 1992, ppl58-179) ... 

The capacity of a chemical to cause harm is what the hazard identification stage of risk assessment is intended to identify - the hazards of a chemical are the adverse effects [harm] which [it] has an inherent capacity to cause (Article 2 of Directive 93/67/EEC). The identification of adverse effects on the health of humans and wildlife relies heavily on tests on laboratory animals. I have already discussed some of the many uncertainties that result from the use of animal tests. A key question is whether there are viable alternatives. Before proposing an alternative testing strategy I first consider animal tests as scientific experiments and ask whether they are good experiments, given what we want to find out. 

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