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1 HEALTH EFFECTS FROM EXPOSURE TO CHRONIC LEVELS OF INDUSTRIAL CHEMICALS Y. Takeuchi Research Center for Radiation Emergency Medicine, National Institute of Radiological Sciences, Chiba, Japan Keywords : Chronic toxicity, Industrial chemicals, Specific toxicity, Neurotoxicity, Reproductive toxicity, Carcinogenicity, Immunotoxicity, n-hexane, 2-Bromopropane, Benzene, Extrapolation from animal data. Contents 1. Definition of Chronic Toxicity 2. Specific Toxicity or Target Organs of Chemicals 3. Cases of Chronic Occupational Poisoning 4. Prevention Glossary Bibliography Biographical Sketch To cite this chapter Summary Chronic health effects on workers are usually caused by repeated exposure to industrial chemicals for a long time at rather low concentrations in the workplace. There is no clear definition about chronic occupational poisoning. Definition of chronic occupational toxicity is introduced from the viewpoint of the ACGIH (American Conference Of Governmental Industrial Hygienists) and the JSOH (Japan Society For Occupational Health). Industrial chemicals have some specific or major toxicity with other minor toxicity. Important, specific, or major toxicity such as neurotoxicity, reproductive toxicity, carcinogenicity, and immunotoxicity of chemicals are described, and industrial chemicals classified by specific toxicity are listed in the tables. Cases of chronic occupational poisoning such as n-hexane polyneuropathy, reproductive disorders due to 2-bromopropane, and leukemia associated to benzene are described as examples to understand health effects from exposure to chronic levels of industrial chemicals. The hygienic standards for industrial chemicals and viewpoints of the ACGIH and JSOH are described. Finally, important issues in extrapolation from data of animal experiments to humans are described. 1. Definition of Chronic Toxicity Chronic health effects on workers are usually caused by repeated exposure of industrial chemicals for a long time at rather low concentrations in the workplace. There is no clear definition about chronic poisoning in terms of exposure period. Usually, health effects of acute poisoning are considered due to less than 5 15 minutes exposure of high concentration such as irritation and narcosis, etc. Sub-chronic poisoning is a rather specific health disorder due to moderate levels of exposure for less than 3 6 months.

2 Chronic poisoning is a health disorder due to low levels of exposure for more than 3 6 months, which sometimes include aftereffects of acute and sub-chronic poisoning, malignant tumors occurring many years after exposure, effects on the following generations, shortening of life span and etc. Generally speaking, chronic poisoning could cause less specific health disorders than a sub-chronic one. Ambient concentrations in the workplace usually fluctuate in a wide range during working hours, day-by-day, and year-by-year. Workers are working 6 8 hours a day, 5 6 days a week, for about years, from starting of work to retirement. Therefore, the health disorders caused by occupational exposure from 3 6 months to years could be regarded as chronic poisoning. However, accurate assessment of long-term exposure might be very difficult because sufficient data of exposure levels are not available in most cases. 2. Specific Toxicity or Target Organs of Chemicals Industrial chemicals have one or more specific or major toxicity with minor toxicity, respectively. Some organs are specifically susceptible to some chemicals. For example, carbon tetrachloride is specifically toxic to the liver, cadmium is toxic to the kidney, benzene is toxic to the haematopoietic organs, n-hexane is toxic to the peripheral nerve, 2-bromopropane is toxic to the reproductive organs, benzene is an agent linked to causes of leukemia, toluenediisocyanate (TDI) is an allergen to cause asthma, and so on. The specific or major toxicity is important to detect early signs of health disorders, and establish the threshold limit values of chemicals to prevent the occupational poisoning, because it is the most sensitive parameters for toxicity of chemicals. However, it should be noted that industrial chemicals have other toxicity apart from major toxicity. Important specific or major toxicity such as neurotoxicity, reproductive toxicity, carcinogenicity, and immunotoxicity of industrial chemicals are described in the following section, and industrial chemicals classified by specific or major toxicity are listed in the tables Neurotoxicity Neurotoxicity is any effects on the structure or function of the central and/or peripheral nervous system related to exposure of a chemical substance. Recently, neurotoxicity has become an important endpoint in hazard identification and assessing the risks of chemicals. The nervous system is of particular interest because mature neurons are generally incapable of regeneration. The disorders of the nervous system due to chronic exposure to industrial chemicals are usually very hard to recover, and sometimes tend to become gradually more serious even after removal from the exposure. In addition, the normal cascade of brain development during fetal and newborn life may be exquisitely sensitive to disruption by chemicals, resulting in lasting and profound nervous system dysfunction. Human exposure to potential neurotoxic substances is increasing public concern. Main neurotoxic chemicals to which workers may be exposed in the workplace are listed in the table (see Table 1). Acrylamide Chemicals Chemicals Mercury, inorganic

3 Alkanes Anesthetic gases, waste Carbaryl Carbon disulfide Carbon monoxide Carbon tetrachloride Chloroform Cresol Dinitro-o-cresol Ethylene dibromide Fluorocarbon polymers, decomposition products Formaldehyde Hydrogen cyanide and salts Hydrogen sulfide Ketones Lead, inorganic/organic Malathion Methyl alcohol Methyl parathion Methyl chloride Nitriles Parathian Petroleum solvents, refined Styrene 1, 1, 2, 2-Tetrachloroethane Tetrachloroethylene Thiols Toluene 1, 1, 1-Trichloroethane Tungsten and cemented tungsten products Xylene Zinc oxide Table 1. Chemicals producing neurotoxic effects at low concentrations Reproductive Toxicity Reproductive toxicity encompasses adverse health effects in the prospective mother, the father, the developing embryo, and infant. The most striking features of reproduction are the myriad of rapid multiplying cells in the ovary, testis, or tissues of the embryo, and such cells to various chemicals would be much more susceptible than would be anticipated to elicit toxicity in other cell systems at low concentration. In reproductive toxicology, it is insufficient to determine that the target site of the agent is the testis, the ovary, and the conception, etc. The various direct and indirect events occurring during the reproductive development cycle, each of these being characterized by multiple components should be examined. Information about reproductive toxicity of industrial chemicals is very limited as yet. Main well-known reproductive toxicants in the workplace are listed in the table (see Table 2). Boron Chemicals associated with male Benzene Chemicals associated with female Aromatic hydrocarbons (e.g. toluene) 2-Bromopropane

4 2-Bromopropane Cadmium Carbon disulfide Carbon monoxide Carbon tetrachloride Carbaryl Chlordecone Chloroprene Dibromochloropropane (DBCP) Dimethyl dichlorovinyl phosphate (DDVP) Epichlorohydrin Estrogens Ethylene oxide Ethylene dibromide (EDB) Ethylene glycol ethers Lead Manganese Polybrominated biphenyls (PBBs) Polychlorinated biphenyls (PCBs) Cadmium Carbon monoxide Carbon disulfide Cytostatic drugs Dibromochloropropane (DBCP) Ethylene glycol Ethylene oxide Halogenated anesthetic gases Lead Mercury Nitrous oxide Manganese Ozone Polybrominated biphenyls (PBBs) Polystyrene Polychlorinated biphenyls (PCBs) Polyurethane Styrene Table 2. Chemicals associated with reproductive disorders Carcinogenicity of Chemicals Cancer ranks as the toxic effects of most concern to the public. Because of this, considerable effort and financial resources are spent annually to identify potential human carcinogens. ACGIH (American Conference of Governmental Industrial Hygienists) classifies occupational carcinogens into A1 to A5. A1 is a confirmed human carcinogen including 18 chemicals. A2 is a suspected human carcinogen including 25 chemicals. A3 is a confirmed animal carcinogen including 83 chemicals. A4 is not classifiable as a human carcinogen including 83 chemicals. A5 is not suspected as a human carcinogen including 2 chemicals. JSOH (Japan Society for Occupational Health) classifies occupational carcinogens into group 1, group 2A, Group 2B according to the criteria of International Agency for Research on Cancer (IARC). Group 1 includes 20 chemicals that are carcinogenic to humans. Group 2A includes 20 chemicals that are probably carcinogenic to humans having more sufficient evidence. Group 2 B includes 103 chemicals that are possibly carcinogenic to humans having less sufficient

5 evidence. Industrial chemicals classified into Group 1 and Group 2A by JSOH are listed in the table (see Table 3). Group 1 (carcinogenic to humans) 4-Aminophenyl Arsenic and compounds Asbestos Benzene Benzidine Benzotrichloride Bis (chloromethyl) ether Cadmium and compounds Chromium (VI) compounds Coal-tar pitches Coal-tars Erionite Ethylene oxide Mineral oils (untreated and mildly treated) 2-Naphthylamine Nickel compounds (except Ni metal) Soots Group 2A (probably carcinogenic to humans) Acrylonitrile Acrylamide Benzo [a] pyrene Beryllium and compounds 1, 3-Butadiene Chloromethyl methyl ether (technical grade) Creosotes 3, 3'-Dichloro-4, 4'- diaminodiphenylmethane (MBOCA) Diethyl sulphate Dimethyl sulphate Dimethylcarbamoyl chloride Epichlorohydrin Formaldehyde P-Chloro-o-toluidine and its strong acid salts Polychlorinated biphenyl (PCB) Sulphur dichlordiethyl Talc containing asbestiform fibers Vinyl chloride Wood dust Silica (crystalline) Styrene oxide Tris phosphate (2, 3-dibromopropyl) Vinyl bromide Vinyl fluoride 2.4. Immunotoxicity Table 3. Occupational carcinogens. Immune system comprises a complex set of cellular and biochemical components that serve to recognize and protect the body against foreign materials. Immunotoxicology is a relatively new science and may be defined as the discipline concerned with

6 understanding the potential deleterious effects of chemical xenobiotics on the immune system. Allergies caused by chemicals in the workplace affect mostly the skin, the respiratory passages, and the conjunctiva. A number of allergens can cause both skin lesions and respiratory symptoms. Contact allergies generally manifest themselves as contact allergic dermatitis. The pathogenesis of contact allergic dermatitis involves a cell-mediated (T lymphocytes) immune reaction of delayed type. Allergic reactions, which develop in the respiratory passage, and on the conjunctiva as bronchial asthma or rhino conjunctivitis are mostly a result of reaction of the allergen with specific antibodies of the IgE class, and belong in their reaction rates to the manifestations of immediate type. Essentially allergen-specific immune complexes of IgG type in which cell-mediated reactions can be involved induce exogenous allergic alveolitis. It is necessary to distinguish between induction and triggering of an allergy. It is still not possible to determine generally applicable threshold concentrations either for the induction of an allergy (sensitization) or for triggering the allergic reaction in an already sensitized person. The likelihood of induction increases with the concentration of the allergen to which persons are occupationally exposed. Much lower concentrations are required to trigger an already existing allergy than for its induction. JSOH also indicates occupational sensitizers in the list. The sensitizers classified by JSOH into Group 1 substances which induce allergic reactions in humans and Group 2 which probably induce allergic reactions in humans are listed in the table (see Table 4). Skin Respiratory passage Group 1 Group 2 Group 1 Group 2 Chromium Benzofuran Beryllium Chromium Cobalt Benzoyl peroxide Cobalt Ethylenediamine Colophony (Rosin) Beryllium Colophony (Rosin) Formaldehyde Ethylenediamine Butyl acrylate Diphenylmethane-4, 4'-diisocyanate Maleic anhydride (MDI) Formaldehyde Copper Glutaldehyde Methyl methacrylate Glutaldehyde Dibutyl phthalate Hexane-1, 6- diisocyanate Nickel Mercury Dichloropropane Phthalic anhydride Piperazine Nickel Ethylene oxide Platinum P- Phenylenediamine Hydrazine Toluenediisocyanates Platinum Hydroquinone Trimellic anhydride Iodine Maleic anhydride Methyl methacrylate

7 Polyvinyl chloride Resorcinol Toluenediisocyanates Turpentine Table 4. Occupational sensitizers. 3. Cases of Chronic Occupational Poisoning Cases of chronic occupational poisoning such as n-hexane polyneuropathy, reproductive disorders due to 2-bromopropane, and leukemia associated to benzene are described as examples to understand health effects from exposure to chronic levels of industrial chemicals in the following section Polyneuropathy Due to n-hexane As petroleum refinery industry rapidly developed in 1960s, many cases of polyneuropathy occurred in the workers exposed to organic solvents containing petroleum distillates. The field surveys and animal experiments revealed that n-hexane, one of the main components in petroleum distillates, is the main agent for causing polyneuropathy. The patient, 21 years old female, started manufacturing vinyl sandals in April 1966, and she was exposed to ppm n-hexane. She noticed sensory disturbance in her extremities about 6 months after starting the job. Unsteady gait and muscle atrophy in lower extremities was noticed in December Her anorexia, weight loss, and gait disturbance developed and she was admitted to hospital in January At that time, she had serious muscle atrophy in her extremities and could not walk by herself. However, she recovered to be able to walk for herself in August She left hospital with slight sensory disturbance and slight muscle atrophy in distal portion of extremities in October The workers manufacturing vinyl sandals in the same district were investigated. The subjective symptoms of 1662 vinyl sandal manufacturers were surveyed by using questionnaire and the suspicious 296 of them were medically examined. Polyneuropathy was found in 93. All cases had sensory disturbance, 40 cases had muscle weakness and 8 cases had muscle atrophy in extremities. The cases were classified into three groups by mode of involvement and exposure concentrations are shown in the table (see Table 5). Mode of involvement Number of patients Exposure concentration of hexane Sensory polyneuropathy ppm Sensory-motor polyneuropathy without muscle atrophy ppm

8 Sensory-motor polyneuropathy with muscle atrophy ppm Table 5. Number of polyneuropathy by mode and exposure concentrations of n-hexane. The results suggested that about 100 ppm n-hexane could cause sensory polyneuropathy, and about 500 ppm n-hexane cause sensory-motor polyneuropathy in workers. The animal experiment in which rats were exposed to 3000 ppm of more than 99% pure n-hexane, n-pentane and n-heptane, 12 hours a day, for 16 weeks, revealed that n- hexane caused the similar peripheral nerve impairment to those of workers, but n- pentane and n-heptane did not. The experiment showed that n-hexane has a specific toxicity to the peripheral nerve Reproductive Disorders Due to 2-Bromopropane An outbreak of reproductive disorders due to 2-bromopropane occurred in a Korean electronic factory in Of 33 workers (8 men and 25 women) exposed to a solvent containing 2-bromopropane in the process of assembling tactile switches, 16 (64%) females had amenorrea, and six (75%) males had azoospermia, oligozoospermia or reduced sperm motility. The average exposure period for female workers was 9.5±3.6 months. The onset of amenorrea was 4 16 months after the introduction of 2- bromopropane in place of Freon 113. The average duration of amenorrea has been 7.1±3.1 months at the first medical examination in July The average exposure period for male workers was 18.2±1. 3 months. Of 8 male workers, two (25%) males had azoospermia four (50%) had oligozoospermia or reduced sperm motility. In the tactile switch assembling process, parts of the switch were dipped in cleaning baths containing the solvent and polytetrafluoroethylene to prevent flux and fume from spreading after soldering. The solvent used in the process contained 97% 2- bromopropane. To estimate the exposure concentrations of the solvent, the air concentrations were measured after setting up simulated conditions. A total of 14 area samples were collected near cleaning solution baths and some automatic assembling machines and analyzed with a gas chromatograph. The mean 2-bromopropane concentrations in 14 area samples was 12.4 ppm (SD 3.1 ppm, range ppm). Short-term exposure levels were monitored inside the hood of the baths for 15 min, and 106, 4101 and 4360 Ppm of 2-bromopropane was detected. Seven baths were used in the process and five of them had been used since before February Next, two baths of seven were introduced in May and August 1994, and they were not equipped with an automated injection system or local ventilation till the end of November The workers using the new baths had to manually supply the solvent to the baths. Under these working conditions, the workers seemed accidentally to be exposed to high concentrations of 2-bromopropane for about 6 months. The 16 patients with amenorrea were investigated 2 years after the fist medical examination. Only 2 patients of 16 recovered ovarian function. One of two delivered a normal full-term baby and the other resumed regular menstrual periods. Ovarian biopsy of the patients with persisting

9 amenorrea showed fibrosis in the ovarian cortex, lack of follicles at various stage of development, irregular atrophy of follicles. Oocytes and granulose cells were not found in the primary follicles. The results showed that the serious disorders of ovary due to high concentration exposure of 2-bromopropane are hard to recover. The animal experiment in which four groups of nine rats each were exposed to 0, 300, and 1000 or 3000 ppm of 2-bromopropane, 8 hours a day, 7 days a week, for 9 weeks, proved that exposure to 2-bromopropane of 300 ppm moderately atrophied testes and decreased all types of germ cells to about a half of the control, 1000 ppm completely lost germ cells and severely atrophied seminiferous tubules. The animal experiment showed that 2-bromopropane has a specific toxic effect on the testes, especially on the spermatogonia. Another animal experiment in which four groups of nine rats each were exposed to 0, 100, 300 or 1000 ppm of 2-bromopropane 8 hours a day, 7 days a week for 9 weeks clarified that 2-bromopropane had the ovarian toxicity in the virgin female rat. The number of normal estrous cycles decreased significantly both in the 300 and 1000 ppm and in the 100 ppm group. In the 1000 ppm group, the most remarkable change in the ovary was atresia of the ovarian follicles accompanied by a decreased number of normal antral and growing follicles. The animal experiment showed that 2- bromopropane has ovarian toxicity in rats. The animal experiment proved that 2- bromopropane is the causative agent for the amenorrea observed in the female workers and azoospermia or oligospermia in the male workers Leukemia Due to Benzene Benzene was first described as a cause of fatal aplastic anemia in Early unregulated exposure to benzene that was used widely as a solvent and starting chemical in the production of many products led to many cases of serious haematopoietic disorders. At exposures of 100 ppm or higher, some workers will develop fatal aplastic anemia. Toxicity is related to the amount and duration of exposure, although there is individual variation in susceptibility. The diagnosis is made by examination of the bone marrow after an abnormal complete blood count is reported. The bone marrow will reveal hypocellularity with fatty replacement. About a half of benzene-related aplastic anemia may recover completely after removal from the exposure in workplace. If hypocelluarity persists for more than several months, recovery is not likely to occur. Exposure to benzene has been associated with the development of acute non-lymphocytic leukemia, chronic myelogenous leukemia, and multiple myeloma. Many cases and epidemiological studies of leukemia related to benzene exposure are reported. However, no sufficient data on exposure concentrations and the number of exposed workers are available. In a rubber hydrochloride plant, 21 workers died of haematopoietic and lymphatic tumors. The cohort consisted of 1717 white men who had been engaged in manufacturing Polio film (rubber hydrochloride) for at least one day. The risk of benzene-induced leukemia was calculated for occupational benzene exposure at 1 ppm for 8 hours a day for 45 years for men between the ages of 20 and 65. It is assumed that Polio film workers had inhaled 10 m 3 airs for 8 hours a day, 250 days a year. The excess death from leukemia was calculated applying a proportional hazards model to a group consisting of 15 cases of death from leukemia among the Polio film workers and to a group of 650 control subjects matched to the case group by factory, sex, age, and starting year of work. The results are shown in the

10 table (see Table 6). From these data, JSOH proposes the reference values corresponding to an individual excess lifetime risk of cancer for benzene as shown in the table (see Table 7). Exposure estimate Cumulative occupational benzene exposure (ppm years) Rinsky et al Crump and Allen Paustenbach et al Estimated number of leukemia deaths over lifetime. Table 6. Excess death from leukemia over lifetime of 1000 benzene-exposed individuals with various exposure assessments. Substance Benzene Individual excess lifetime risk of cancer Reference value ppm ppm Method of estimation Average relative risk model Year of estimation 1997 Table 7. Reference values corresponding to an individual excess lifetime risk of cancer. 4. Prevention 4.1. Hygienic Standard to Prevent Chronic Occupational Poisoning About 100,000 chemicals are used in industry but only limited data of their chronic toxicity to humans are available. ACGIH proposes threshold limit values (TLVs) for many chemicals to prevent occupational poisoning, and defines that TLVs refer to airborne concentrations of substances and represent conditions under which it is believed that nearly all workers may be repeatedly exposed day by day without adverse health effects. JSOH defines that occupational exposure limit-mean (OEL-M) is the reference value to the mean exposure concentration at or below which adverse health effects caused by the substance do not appear in most workers for 8 hours a day, 40 hours a week under moderate workload. If mean levels and duration of exposure corresponding to segments of various jobs can be measured or estimated, then an overall exposure concentration can be determined as the time-weighted average concentration. The time-weighted average concentration for a conventional 8-hour workday and a 40-hour workweek are used as an index for exposure concentration to set the threshold limit value for working period of years. However, many researchers consider that carcinogens do not have the threshold at or less which it could not cause the excess carcinoma. Therefore, the threshold values are proposed for only small number of carcinogens, but are not for most carcinogens. ACGIH proposes TLVs for

11 693 chemicals based on some evidence of its dose-dependent toxicity or carcinogenicity. However, in comparison with the number of available industrial chemicals, the number of the proposed chemicals is too small. Moreover, about 1000 new chemicals are introduced into industry every recent year Extrapolation from Data of Animal Experiment to Humans In addition to epidemiological data of workers, it is indispensable to extrapolate the data of experimental animals to humans in spite of wide differences between them for proving or clarifying the toxicity of chemicals. There is no definite standard for experimental design for chronic animal experiments. An example of a design for chronic animal experiments is shown in the table (see Table 8). The uncertainty factor (UF) of 10 may be applied for the uncertainty in extrapolating experimental animals to humans, data in sub-chronic exposure study to those in chronic exposure, and LOAEL (lowest observed adverse effect level) to NOAEL (no-observed adverse effect level), respectively. Glossary ACGIH: IARC: JSOH: LOAEL: NOAEL: OEL: TLV: UF: Number of animals Clinical Concentration Exposure Group Laboratory or dose Male Female period studies 1 Control 10 (50) 10 (50) 2 Low 10 (50) 10 (50) 6 or 12 3, 6, and 12 months 3 Mid 10 (50) 10 (50) months (2 years) 4 High 10 (50) 10 (50) Number of animals and exposure period in parenthesis are those in carcinogenic test. Table 8. A design of chronic toxicity study in animals. American Conference of Governmental Industrial Hygienists. International Agency for Research on Cancer. Japan Society for Occupational Health. Lowest Observed Adverse Effect Level. No-Observed Adverse Effect Level. Occupational Exposure Limit. Threshold Limit Value. Uncertainty Factor. Bibliography ACGIH (1999). Threshold limit values for chemical substances and physical agents, Biological Exposure Indices Cincinnati: ACGIH. [This recommends threshold limits values of many chemicals in the workplace.] Ellenhorn M. J. (1997). Principles of poison management; the pregnant patient. Ellenhorn s Medical Toxicology 2nd Ed. pp Baltimore: Williams and Wilkins. [This presents reproductive toxicity of many chemicals and their classification based on human and animal evidence.]

12 JSOH (1999). Recommendation of Occupational Exposure Limits ( ). Journal of Occupational Health 41, [This recommends occupational exposure limits of many chemicals in Japan.] Kaneko T., Wang P. T., and Sato A. (1997). Benzene-Associated Leukemia and its Risk Assessment. Journal of Occupational Health 39, [This presents a comprehensive risk-assessment of benzene exposure in the workplace.] Koh J. M., Kim C. H., Hong S. K., Lee K. U., Kim Y. T., Kim O. J., and Kim G. S. (1998). Primary Ovarian Failure Caused by a Solvent Containing 2-Bromopropane. European Journal of Endocrinology 138, [This presents 2 years follow-up study on the patients with amenorrea caused by 2- bromopropane exposures in Korea.] Schulze G. E. (1995). Neurotoxicity. CRC Handbook of Toxicology (eds. Derelanko M. D. and Hollinger M. A.) pp New York: CRC press. [This presents a comprehensive description on neurotoxicity of many chemicals.] Takeuchi Y., Ono Y., Hisanaga N., Kitoh J., and Sugiura Y. (1980). A Comparative Study on the Neurotoxicity of N-Pentane, N-Hexane, and N-Heptane in the Rat. British Journal of Industrial Medicine 37, [This presents specific neurotoxicity of n-hexane compared with n-pentane and heptane in rats.] Takeuchi Y., Ichihara G., and Shibata E. (1997a). Modification of Hexane Neurotoxicity by Other Organic Solvents, its Mechanism, and Risk Assessment. Advances in Occupational Medicine and Rehabilitation 3(3), [This presents dose-response relationship of n-hexane polyneuropathy occurred in vinyl sandal manufacturers in Japan.] Takeuchi Y., Ichihara G., and Kamijima M. (1997b). A Review on Toxicity of 2-Bromopropane: Mainly on its Reproductive Toxicity. Journal of Occupational Health 39, [This presents the reproductive toxicity of 2-bromopropane based on the cases of workers and the results of animal experiments.] Thomas P., and House R. V. (1995). Pre-clinical Immunotoxicity Assessment. CRC Handbook of Toxicology (eds. Derelanko M. D. and Hollinger M. A) pp New York: CRC press. [This presents immunotoxicity assessment of many chemicals.] Biographical Sketch Dr. Yasuhiro Takeuchi is Director of Research Center for Radiation Emergency Medicine, National Institute of Radiological Sciences, Chiba, Japan. His main research fields are Occupational and Environmental Health, Organic solvent poisoning (n-hexane polyneuropathy, Toluene-induced CNS impairment, Reproductive toxicity of bromopropanes, etc), Neurotoxicology of industrial chemicals, Reproductive toxicology of chemicals, Occupational contact dermatitis, and Occupational health problems in small enterprises. To cite this chapter Y. Takeuchi, (2004), HEALTH EFFECTS FROM EXPOSURE TO CHRONIC LEVELS OF INDUSTRIAL CHEMICALS, in Environmental Toxicology and Human Health, [Ed. Tetsuo Satoh], in Encyclopedia of Life Support Systems (EOLSS), Developed under the Auspices of the UNESCO, Eolss Publishers, Oxford,UK, [