Chronic toxicity—

Chronic toxicity studies provide information on the long-term health effects of chemical substances. Adverse health effects in exposed animals and subsequent severe damage are known to occur after repeated exposure to low doses over a period of time. The slow accumulation of mercury or lead in the body or after a long latency period from exposure to chemical carcinogens is an example. Chronic or prolonged periods of exposure to chemical substances may also cause adverse effects on the reproduction and behavior of animals and humans. The symptoms caused after chronic exposure usually differ from those observed in acute poisoning from the same chemical. In fact, when exposed to low concentrations of chemical substances, as is the case with chronic toxicity studies, the industrial worker and common public are unaware of the exposure. 

The details of several other toxicological tests (namely, repeated-dose toxicity, subchronic toxicity, chronic toxicity, genotoxicity, mutagenicity, teratogenicity, carcinogenicity, neurotoxicity, and ecotoxicology) and the methods, purposes, and importance of safety evaluation studies to achieve human health have been discussed 

The routes of administration should be the same as proposed in the protocol as well as by labeling. This, however, as in some of the studies, requires modifications (e.g., drench in lieu of medicated feeds). In order to minimize autolytic decomposition, necropsy should be performed promptly after death on all animals that die during the study. The necropsy should be performed by a qualified and experienced person. A complete physical examination should be performed, and baseline data should be collected by a qualified and trained worker. Data should be obtained prior to the start of the trial and at reasonable, predetermined intervals thereafter in accordance with the study protocol. 

The clinical observations should be recorded twice daily, 7 days a week, during the entire study period, or according to the study protocol. Appropriate clinical pathologic procedures should be conducted on all test groups. This is required on all animals in each group or, when appropriate, on a representative number (usually 

Documentation of all studies should be made indicating the representative test conditions and the manner of use of the test chemical substance. It is very important to remember that more often than not, the toxicological effects observed in animals and humans caused by chemical substances involve various modulating factors. Over the years, the potential health risks that might be caused by chemical substances acting in combination have been found to be important. In fact, the interaction between chemical substances does take many forms. Such interactions between chemical substances have become very relevant to determine the potential health risks vis-a-vis human safety. Some of the known and common forms of interactions include the following four categories  

Pesticide LC50 (Pg/L) Acute Toxicity Chronic Value ( xg/L) ACR Chronic Toxicity 

Preview This section provides a brief introduction to chronic toxicity and why it is important to understand this type of toxicity when working with chemicals over longer periods of time. 

There can be no intelligent control of the lead danger in industry unless it is based on the principle of keeping the air clear from dust and fumes. 

INCIDENT 4.2.1.2 CHRONIC TOXICITY FROM TCDD EXPOSURE  

What lessons can be learned from these incidents  

In your work in the laboratory, you will encounter chemicals that have documented or suspected toxic effects due to relatively low exposures over longer periods of time. These are chronic toxicants as introduced in Section 4.1.1. While the incident described above illustrates an adverse outcome from exposure to a chronic toxicant, these cases are rare in laboratories. The nature of the effects from exposures to chronic 

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CioHjjNOi. White crystals, m.p. 137-138°C. Prepared from phenol, via />-nitro-phenol, p-nitrophenetole and /7-phenetidine. It is used medicinally as an antipyretic analgesic similar to aspirin. It has chronic toxicity towards the kidney. 

Because of the corrosive effects and discomfort associated with inhalation of fluorine, chronic toxicity does not occur. Although the metaboHc fate of fluorine is not clear, it does not seem that much is converted to fluoride ion in the body (107). Therefore comparisons to effects of fluoride ion poisoning, known as fluorosis, are probably incorrect. 

The toxicity of these fluoroaluminates is mainly as inorganic fluorides. The ACGIH adopted (1992—1993) values for fluorides as F is TLV 2.5 mg/m. The oral toxicity in laboratory animal tests is reported to be LD q rat 2.15 mg/kg (41). Because of the fine nature of the products they can also be sources of chronic toxicity effects as dusts. 

The acute and chronic toxicity of hydraziae, the methyUiydraziaes, phenylhydraziae, and other hydraziae derivatives has received extensive study, and is comprehensively covered ia several reviews (159—163). 

In additional EPA studies, subchronic inhalation was evaluated ia the rat for 4 and 13 weeks, respectively, and no adverse effects other than nasal irritation were noted. In the above-mentioned NTP chronic toxicity study ia mice, no chronic toxic effects other than those resulting from bronchial irritation were noted. There was no treatment-related increase ia tumors ia male mice, but female mice had a slight increase in bronchial tumors. Neither species had an increase in cancer. Naphthalene showed no biological activity in other chemical carcinogen tests, indicating Htde cancer risk (44). No incidents of chronic effects have been reported as a result of industrial exposure to naphthalene (28,41). 

Chronic Toxicity. The effects of repeated oral exposure to phthalates for periods ranging from a few days to 2 years have been studied in a number of animal species including rats, mice, hamsters, guinea pigs, ferrets, and dogs (37). 

The majority of studies on the acute and chronic toxicity of phthalates to aquatic organisms show no toxic effects at concentrations 200—1000 times the water solubiUty. However, there are some studies iadicatiag higher toxicity which are beheved to be due to the flotation and entrapment effects outlined above. 

The health effects of sorbic acid and sorbates have been reviewed (165—167). The extremely low toxicity of sorbic acid enhances its desirabiHty as a food preservative. The oral LD q for sorbic acid in rats is 7—10 g/kg body weight compared to 5 g/kg for sodium chloride (165—169). In subacute and chronic toxicity tests in rats, 5% sorbic acid in the diet results in no abnormal effects after 90 days or lifetime feeding studies. A level of 10% in rat diets results in a slight enlargement of the Hver, kidneys, and thyroid gland (170). This same dietary level fed to mice also resulted in an increase in Hver and kidney weight... 

In 1969, a chronic toxicity study on a cyclamate saccharin (10 1) blend indicated bladder cancer problems in rats. Cyclamate was soon banned by the FDA, but saccharin remained an approved sweetener. In 1977, the FDA proposed a ban on saccharin because of the discovery of bladder tumors in some male rats fed with high doses of saccharin. Because no other nonnutritive sweetener was available at that time, the proposed ban faced strong opposition. 

Chronic Toxicity Studies. With the exception of tumorigenesis, most types of repeated exposure toxicity are detected by subchronic exposure conditions. Therefore, chronic exposure conditions are usually conducted for the following reasons if there is a need to investigate the tumorigenic potential of a material if it is necessary to determine a no-effects or threshold level of toxicity for lifetime exposure to a material and if there is reason to suspect that particular forms of toxicity are exhibited only under chronic exposure conditions. 

Vanadium compounds, including those which may be involved in the production, processing, and use of vanadium and vanadium alloys, are irritants chiefly to the conjuctivae and respiratory tract. Prolonged exposure may lead to pulmonary compHcations. However, responses are acute, never chronic. Toxic effects vary with the vanadium compound involved. For example, LD q (oral) of vanadium pentoxide dust in rats is 23 mg/kg of body weight (24). 

Vanillin has a low potential for acute and chronic toxicity, with a reported oral LD q in rats of 1580—3300 mg/kg. Dietary doses up to 20,000 ppm adrninistered to rats for two years resulted in no adverse toxicologic or carcinogenic effects. Vanillin is classified as a GRAS substance by EEMA. Consequently, at levels normally found in the human diet, vanillin would present no significant health or carcinogenic risk to humans. 

Chronic toxicity in laboratory animals by two-year or lifetime feedings in two species of laboratory animals, multiple-generation teratogenicity, and, not always required, one-year feeding of dogs. 

Effluent toxicity can also be defined as a chronic toxicity in which the growth or reproduction rate of the species is affected. 

A number of antioxidants have been accepted by the FDA as indirect additives for polymers used in food appHcations. Acceptance is deterrnined by subchronic or chronic toxicity in more than one animal species and by the concentration expected in the diet, based on the amount of the additive extracted from the polymer by typical foods or solvents that simulate food in their extractive effects. Only materials of insignificant risk to the consumer are regulated by the FDA for use in plastics contacted by food stuffs. 

Acute and Chronic Toxicity. Although chromium displays nine oxidation states, the low oxidation state compounds, -II to I, all require Special conditions for existence and have very short lifetimes in a normal environment. This is also tme for most organ ochromium compounds, ie, compounds containing Cr—C bonds. Chromium compounds that exhibit stabiUty under the usual ambient conditions are limited to oxidation states II, III, IV, V, and VI. Only Cr(III) and Cr(VI) compounds are produced in large quantities and are accessible to most of the population. Therefore, the toxicology of chromium compounds has been historically limited to these two states, and virtually all of the available information is about compounds of Cr(III) and/or Cr(VI) (59,104). However, there is some indication that Cr(V) may play a role in chromium toxicity (59,105—107). Reference 104 provides an overview and summary of the environmental, biological, and medical effects of chromium and chromium compounds as of the late 1980s. 

Both acute and chronic toxicity testing of the treated effluent on daphnia shrimp and fathead minnows have indicated that the effluent is completely suitable for discharge into receiving waters with no adverse impact (42). 

K. J. Maeek, K. S. Buxton, S. S. Sauter, S. Gnilka and J. W. Dean, Chronic Toxicity of Atrazine to Selected Aquatic Invertebrates and Pishes, Environmental Researeh Laboratory, US Environmental Proteetion Ageney, Deluth, MN, 1976, EPA 600/3-76-047. 

The full extent of the toxicity of pesticides to aquatic life is not known. Although chronic toxicity testing is required for new substances, little is known about the long-term effects of older pesticides. Also, very little is known about the toxicity and occurrence of the products formed when pesticides break down (metabolites) or the many non-pesticidal additives (co-formulants and adjuvants) used in pesticide formulations. However, the future is looking brighter. New modelling techniques, EQS development, and the involvement of the NRA in the pesticide registration process, coupled with the development of newer, less persistent pesticides with lower dose rates, all should help to reduce the risk of pesticide pollution. 

The handling of the monomer presents a number of problems. The monomer will polymerise on storage even under an inert gas. Polymer deposition may be observed after standing for less than a day. Exposure to air, to water or to light will accelerate polymerisation. A number of phenolic materials are effective inhibitors, a typical example being 0.02% p-methoxyphenol. Exposure to light, air and water must, however, still be avoided. The monomer has an anaesthetic action and chronic toxic properties and care must therefore be taken in its handling. 

CHRONIC TOXICITY Advcfsc health effects resulting from repeated daily exposures to a chemical for a significant period. 

Polymerization Exothermic reaction which, unless carefully controlled, can run-away and create a thermal explosion or vessel overpressurization Refer to Table 7.20 for common monomers Certain processes require polymerization of feedstock at high pressure, with associated hazards Many vinyl monomers (e.g. vinyl chloride, acrylonitrile) pose a chronic toxicity hazard Refer to Table 7.19 for basic precautions... 

Upper LEVEL 1 Chronic toxicity Toxicity in soil and plants Additional mutagenicity Long-term toxicity Bioaccumulation Inherent biodegradability Additional abiotic degradability 100 t/annum or 500 t cumulative... 

Additional chronic toxicity Additional environmentally dangerous properties Toxicity to birds Long-term toxicity in water and soil Degradability simulation tests Additional abiotic degradability Mobility in water, soil and air cumulative... 

Rockville Pike than 50,000 potentially toxic chemicals. Building 38A Source for basic acute and chronic toxicity... 

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