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Principles of Hazard Identification: The Japanese Approach

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As in many other countries, risk due to exposure to chemicals is regulated in Japan according to the category of chemicals concerned, as listed in table 1. The governmental ministry or agency in charge varies. In the case of industrial chemicals in general, the major law that applies is the Law Concerning Examination and Regulation of Manufacture, Etc. of Chemical Substances, or Chemical Substances Control Law (CSCL) for short. The agencies in charge are the Ministry of International Trade and Industry and the Ministry of Health and Welfare. In addition, the Labour Safety and Hygiene Law (by the Ministry of Labour) provides that industrial chemicals should be examined for possible mutagenicity and, if the chemical in concern is found to be mutagenic, the exposure of workers to the chemical should be minimized by enclosure of production facilities, installation of local exhaust systems, use of protective equipment, and so on.

Table 1. Regulation of chemical substances by laws, Japan

Category Law Ministry
Food and food additives Foodstuff Hygiene Law MHW
Pharmaceuticals Pharmaceuticals Law MHW
Narcotics Narcotics Control Law MHW
Agricultural chemicals Agricultural Chemicals Control Law MAFF
Industrial chemicals Chemical Substances Control Law MHW & MITI
All chemicals except for radioactive substances Law concerning Regulation of
House-Hold Products Containing
Hazardous Substances
Poisonous and Deleterious
Substances Control Law
Labour Safety and Hygiene Law
MHW

MHW

MOL
Radioactive substances Law concerning Radioactive Substances STA

Abbreviations: MHW—Ministry of Health and Welfare; MAFF—Ministry of Agriculture, Forestry and Fishery; MITI—Ministry of International Trade and Industry; MOL—Ministry of Labour; STA—Science and Technology Agency.

Because hazardous industrial chemicals will be identified primarily by the CSCL, the framework of tests for hazard identification under CSCL will be described in this section.

The Concept of the Chemical SubstanceControl Law

The original CSCL was passed by the Diet (the parliament of Japan) in 1973 and took effect on 16 April 1974. The basic motivation for the Law was the prevention of environmental pollution and resulting human health effects by PCBs and PCB-like substances. PCBs are characterized by (1) persistency in the environment (poorly biodegradable), (2) increasing concentration as one goes up the food chain (or food web) (bioaccumulation) and (3) chronic toxicity in humans. Accordingly, the Law mandated that each industrial chemical be examined for such characteristics prior to marketing in Japan. In parallel with the passage of the Law, the Diet decided that the Environment Agency should monitor the general environment for possible chemical pollution. The Law was then amended by the Diet in 1986 (the amendment taking effect in 1987) in order to harmonize with actions of the OECD regarding health and the environment, the lowering of non-tariff barriers in international trade and especially the setting of a minimum premarketing set of data (MPD) and related test guidelines. The amendment was also a reflection of observation at the time, through monitoring of the environment, that chemicals such as trichloroethylene and tetrachloroethylene, which are not highly bioaccumulating although poorly biodegradable and chronically toxic, can pollute the environment; these chemical substances were detected in groundwater nationwide.

The Law classifies industrial chemicals into two categories: existing chemicals and new chemicals. The existing chemicals are those listed in the “Existing Chemicals Inventory” (established with the passage of the original Law) and number about 20,000, the number depending on the way some chemicals are named in the inventory. Chemicals not in the inventory are called new chemicals. The government is responsible for hazard identification of the existing chemicals, whereas the company or other entity that wishes to introduce a new chemical into the market in Japan is responsible for hazard identification of the new chemical. Two governmental ministries, the Ministry of Health and Welfare (MHW) and the Ministry of International Trade and Industry (MITI), are in charge of the Law, and the Environment Agency can express its opinion when necessary. Radioactive substances, specified poisons, stimulants and narcotics are excluded because they are regulated by other laws.

Test System Under CSCL

The flow scheme of examination is depicted in figure 1, which is a stepwise system in principle. All chemicals (for exceptions, see below) should be examined for biodegradability in vitro. In case the chemical is readily biodegradable, it is considered “safe”. Otherwise, the chemical is then examined for bioaccumulation. If it is found to be “highly accumulating,” full toxicity data are requested, based on which the chemical will be classified as a “Class 1 specified chemical substance” when toxicity is confirmed, or a “safe” one otherwise. The chemical with no or low accumulation will be subject to toxicity screening tests, which consist of mutagenicity tests and 28-day repeated dosing to experimental animals (for details, see table 2). After comprehensive evaluation of the toxicity data, the chemical will be classified as a “Designated chemical substance” if the data indicate toxicity. Otherwise, it is considered “safe”. When other data suggest that there is a great possibility of environmental pollution with the chemical in concern, full toxicity data are requested, from which the designated chemical will be reclassified as “Class 2 specified chemical substance” when positive. Otherwise, it is considered “safe”. Toxicological and ecotoxicological characteristics of “Class 1 specific chemical substance,” “Class 2 specific chemical substance” and “Designated chemical substance” are listed in table 3 together with outlines of regulatory actions.

Figure 1. Scheme of examination

TOX260F1

Table 2. Test items under the Chemical Substance Control Law, Japan

Item Test design
Biodegradation For 2 weeks in principle, in vitro, with activated
sludge
Bioaccumulation For 8 weeks in principle, with carp
Toxicity screening
Mutagenicity tests
Bacterial system
Chromosome aberration


Ames’ test and test with E. coli, ± S9 mix
CHL cells, etc., ±S9 mix
28-day repeated dosing Rats, 3 dose levels plus control for NOEL,
2 weeks recovery test at the highest dose level in addition

Table 3. Characteristics of classified chemical substances and regulations under the Japanese Chemical Substances Control Law

Chemical substance Characteristics Regulation
Class 1
specified chemical substances
Nonbiodegradability
High bioaccumulation
Chronic toxicity
Authorization to manufacture or import necessary1
Restriction in use
Class 2
specified chemical substances
Nonbiodegradability
Non- or low bioaccumulation Chronic toxicity
Suspected environmental pollution
Notification on scheduled manu-facturing or import quantity
Technical guideline to prevent pollution/heath effects
Designated chemical substances Nonbiodegradability
Non- or low bioaccumulation
Suspected chronic toxicity
Report on manufacturing or import quantity
Study and literature survey

1 No authorization in practice.

Testing is not required for a new chemical with a limited use amount (i.e., less than 1,000 kg/company/year and less than 1,000 kg/year for all of Japan). Polymers are examined following the high molecular-weight compound flow scheme, which is developed with an assumption that chances are remote for absorption into the body when the chemical has a molecular weight of greater than 1,000 and is stable in the environment.

Results of Classification of Industrial Chemicals,as of 1996

In the 26 years from the time CSCL went into effect in 1973 to the end of 1996, 1,087 existing chemical items were examined under the original and amended CSCL. Among the 1,087, nine items (some are identified by generic names) were classified as “Class 1 specified chemical substance”. Among those remaining, 36 were classified as “designated”, of which 23 were reclassified as “Class 2 specified chemical substance” and another 13 remained as “designated”. The names of Class 1 and 2 specified chemical substances are listed in figure 2. It is clear from the table that most of the Class 1 chemicals are organochlorine pesticides in addition to PCB and its substitute, except for one seaweed killer. A majority of the Class 2 chemicals are seaweed killers, with the exceptions of three once widely used chlorinated hydrocarbon solvents.

Figure 2. Specified and designated chemical substances under the Japanese Chemical Substances Control Law

TOX260T4

In the same period from 1973 to the end of 1996, about 2,335 new chemicals were submitted for approval, of which 221 (about 9.5%) were identified as “designated”, but none as Class 1 or 2 chemicals. Other chemicals were considered “safe” and approved for manufacturing or import.

 

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Contents

Toxicology References

Andersen, KE and HI Maibach. 1985. Contact allergy predictive tests on guinea pigs. Chap. 14 in Current Problems in Dermatology. Basel: Karger.

Ashby, J and RW Tennant. 1991. Definitive relationships among chemical structure, carcinogenicity and mutagenicity for 301 chemicals tested by the US NTP. Mutat Res 257:229-306.

Barlow, S and F Sullivan. 1982. Reproductive Hazards of Industrial Chemicals. London: Academic Press.

Barrett, JC. 1993a. Mechanisms of action of known human carcinogens. In Mechanisms of Carcinogenesis in Risk Identification, edited by H Vainio, PN Magee, DB McGregor, and AJ McMichael. Lyon: International Agency for Research on Cancer (IARC).

—. 1993b. Mechanisms of multistep carcinogenesis and carcinogen risk assessment. Environ Health Persp 100:9-20.

Bernstein, ME. 1984. Agents affecting the male reproductive system: Effects of structure on activity. Drug Metab Rev 15:941-996.

Beutler, E. 1992. The molecular biology of G6PD variants and other red cell defects. Annu Rev Med 43:47-59.

Bloom, AD. 1981. Guidelines for Reproductive Studies in Exposed Human Populations. White Plains, New York: March of Dimes Foundation.

Borghoff, S, B Short and J Swenberg. 1990. Biochemical mechanisms and pathobiology of a-2-globulin nephropathy. Annu Rev Pharmacol Toxicol 30:349.

Burchell, B, DW Nebert, DR Nelson, KW Bock, T Iyanagi, PLM Jansen, D Lancet, GJ Mulder, JR Chowdhury, G Siest, TR Tephly, and PI Mackenzie. 1991. The UPD-glucuronosyltransferase gene superfamily: Suggested nomenclature based on evolutionary divergence. DNA Cell Biol 10:487-494.

Burleson, G, A Munson, and J Dean. 1995. Modern Methods in Immunotoxicology. New York: Wiley.

Capecchi, M. 1994. Targeted gene replacement. Sci Am 270:52-59.

Carney, EW. 1994. An integrated perspective on the developmental toxicity of ethylene glycol. Rep Toxicol 8:99-113.

Dean, JH, MI Luster, AE Munson, and I Kimber. 1994. Immunotoxicology and Immunopharmacology. New York: Raven Press.

Descotes, J. 1986. Immunotoxicology of Drugs and Chemicals. Amsterdam: Elsevier.

Devary, Y, C Rosette, JA DiDonato, and M Karin. 1993. NFkB activation by ultraviolet light not dependent on a nuclear signal. Science 261:1442-1445.

Dixon, RL. 1985. Reproductive Toxicology. New York: Raven Press.

Duffus, JH. 1993. Glossary for chemists of terms used in toxicology. Pure Appl Chem 65:2003-2122.

Elsenhans, B, K Schuemann, and W Forth. 1991. Toxic metals: Interactions with essential metals. In Nutrition, Toxicity and Cancer, edited by IR Rowland. Boca-Raton: CRC Press.

Environmental Protection Agency (EPA). 1992. Guidelines for exposure assessment. Federal Reg 57:22888-22938.

—. 1993. Principles of neurotoxicity risk assessment. Federal Reg 58:41556-41598.

—. 1994. Guidelines for Reproductive Toxicity Assessment. Washington, DC: US EPA: Office of Research and Development.

Fergusson, JE. 1990. The Heavy Elements. Chap. 15 in Chemistry, Environmental Impact and Health Effects. Oxford: Pergamon.

Gehring, PJ, PG Watanabe, and GE Blau. 1976. Pharmacokinetic studies in evaluation of the toxicological and environmental hazard of chemicals. New Concepts Saf Eval 1(Part 1, Chapter 8):195-270.

Goldstein, JA and SMF de Morais. 1994. Biochemistry and molecular biology of the human CYP2C subfamily. Pharmacogenetics 4:285-299.

Gonzalez, FJ. 1992. Human cytochromes P450: Problems and prospects. Trends Pharmacol Sci 13:346-352.

Gonzalez, FJ, CL Crespi, and HV Gelboin. 1991. cDNA-expressed human cytochrome P450: A new age in molecular toxicology and human risk assessment. Mutat Res 247:113-127.

Gonzalez, FJ and DW Nebert. 1990. Evolution of the P450 gene superfamily: Animal-plant “warfare,” molecular drive, and human genetic differences in drug oxidation. Trends Genet 6:182-186.

Grant, DM. 1993. Molecular genetics of the N-acetyltransferases. Pharmacogenetics 3:45-50.

Gray, LE, J Ostby, R Sigmon, J Ferrel, R Linder, R Cooper, J Goldman, and J Laskey. 1988. The development of a protocol to assess reproductive effects of toxicants in the rat. Rep Toxicol 2:281-287.

Guengerich, FP. 1989. Polymorphism of cytochrome P450 in humans. Trends Pharmacol Sci 10:107-109.

—. 1993. Cytochrome P450 enzymes. Am Sci 81:440-447.

Hansch, C and A Leo. 1979. Substituent Constants for Correlation Analysis in Chemistry and Biology. New York: Wiley.

Hansch, C and L Zhang. 1993. Quantitative structure-activity relationships of cytochrome P450. Drug Metab Rev 25:1-48.

Hayes AW. 1988. Principles and Methods of Toxicology. 2nd ed. New York: Raven Press.

Heindell, JJ and RE Chapin. 1993. Methods in Toxicology: Male and Female Reproductive Toxicology. Vol. 1 and 2. San Diego, Calif.: Academic Press.

International Agency for Research on Cancer (IARC). 1992. Solar and ultraviolet radiation. Lyon: IARC.

—. 1993. Occupational Exposures of Hairdressers and Barbers and Personal Use of Hair Colourants: Some Hair Dyes, Cosmetic Colourants, Industrial Dyestuffs and Aromatic Amines. Lyon: IARC.

—. 1994a. Preamble. Lyon: IARC.

—. 1994b. Some Industrial Chemicals. Lyon: IARC.

International Commission on Radiological Protection (ICRP). 1965. Principles of Environmental Monitoring Related to the Handling of Radioactive Materials. Report of Committee IV of The International Commission On Radiological Protection. Oxford: Pergamon.

International Program on Chemical Safety (IPCS). 1991. Principles and Methods for the Assessment of Nephrotoxicity Associated With Exposure to Chemicals, EHC 119. Geneva: WHO.

—. 1996. Principles and Methods for Assessing Direct Immunotoxicity Associated With Exposure to Chemicals, EHC 180. Geneva: WHO.

Johanson, G and PH Naslund. 1988. Spreadsheet programming - a new approach in physiologically based modeling of solvent toxicokinetics. Toxicol Letters 41:115-127.

Johnson, BL. 1978. Prevention of Neurotoxic Illness in Working Populations. New York: Wiley.

Jones, JC, JM Ward, U Mohr, and RD Hunt. 1990. Hemopoietic System, ILSI Monograph, Berlin: Springer Verlag.

Kalow, W. 1962. Pharmocogenetics: Heredity and the Response to Drugs. Philadelphia: WB Saunders.

—. 1992. Pharmocogenetics of Drug Metabolism. New York: Pergamon.

Kammüller, ME, N Bloksma, and W Seinen. 1989. Autoimmunity and Toxicology. Immune Dysregulation Induced By Drugs and Chemicals. Amsterdam: Elsevier Sciences.

Kawajiri, K, J Watanabe, and SI Hayashi. 1994. Genetic polymorphism of P450 and human cancer. In Cytochrome P450: Biochemistry, Biophysics and Molecular Biology, edited by MC Lechner. Paris: John Libbey Eurotext.

Kehrer, JP. 1993. Free radicals as mediators of tissue injury and disease. Crit Rev Toxicol 23:21-48.

Kellerman, G, CR Shaw, and M Luyten-Kellerman. 1973. Aryl hydrocarbon hydroxylase inducibility and bronochogenic carcinoma. New Engl J Med 289:934-937.

Khera, KS. 1991. Chemically induced alterations maternal homeostasis and histology of conceptus: Their etiologic significance in rat fetal anomalies. Teratology 44:259-297.

Kimmel, CA, GL Kimmel, and V Frankos. 1986. Interagency Regulatory Liaison Group workshop on reproductive toxicity risk assessment. Environ Health Persp 66:193-221.

Klaassen, CD, MO Amdur and J Doull (eds.). 1991. Casarett and Doull´s Toxicology. New York: Pergamon Press.

Kramer, HJ, EJHM Jansen, MJ Zeilmaker, HJ van Kranen and ED Kroese. 1995. Quantitative methods in toxicology for human dose-response assessment. RIVM-report nr. 659101004.

Kress, S, C Sutter, PT Strickland, H Mukhtar, J Schweizer, and M Schwarz. 1992. Carcinogen-specific mutational pattern in the p53 gene in ultraviolet B radiation-induced squamous cell carcinomas of mouse skin. Cancer Res 52:6400-6403.

Krewski, D, D Gaylor, M Szyazkowicz. 1991. A model-free approach to low-dose extrapolation. Env H Pers 90:270-285.

Lawton, MP, T Cresteil, AA Elfarra, E Hodgson, J Ozols, RM Philpot, AE Rettie, DE Williams, JR Cashman, CT Dolphin, RN Hines, T Kimura, IR Phillips, LL Poulsen, EA Shephare, and DM Ziegler. 1994. A nomenclature for the mammalian flavin-containing monooxygenase gene family based on amino acid sequence identities. Arch Biochem Biophys 308:254-257.

Lewalter, J and U Korallus. 1985. Blood protein conjugates and acetylation of aromatic amines. New findings on biological monitoring. Int Arch Occup Environ Health 56:179-196.

Majno, G and I Joris. 1995. Apoptosis, oncosis, and necrosis: An overview of cell death. Am J Pathol 146:3-15.

Mattison, DR and PJ Thomford. 1989. The mechanism of action of reproductive toxicants. Toxicol Pathol 17:364-376.

Meyer, UA. 1994. Polymorphisms of cytochrome P450 CYP2D6 as a risk factor in carcinogenesis. In Cytochrome P450: Biochemistry, Biophysics and Molecular Biology, edited by MC Lechner. Paris: John Libbey Eurotext.

Moller, H, H Vainio and E Heseltine. 1994. Quantitative estimation and prediction of risk at the International Agency for Research on Cancer. Cancer Res 54:3625-3627.

Moolenaar, RJ. 1994. Default assumptions in carcinogen risk assessment used by regulatory agencies. Regul Toxicol Pharmacol 20:135-141.

Moser, VC. 1990. Screening approaches to neurotoxicity: A functional observational battery. J Am Coll Toxicol 1:85-93.

National Research Council (NRC). 1983. Risk Assessment in the Federal Government: Managing the Process. Washington, DC: NAS Press.

—. 1989. Biological Markers in Reproductive Toxicity. Washington, DC: NAS Press.

—. 1992. Biologic Markers in Immunotoxicology. Subcommittee on Toxicology. Washington, DC: NAS Press.

Nebert, DW. 1988. Genes encoding drug-metabolizing enzymes: Possible role in human disease. In Phenotypic Variation in Populations, edited by AD Woodhead, MA Bender, and RC Leonard. New York: Plenum Publishing.

—. 1994. Drug-metabolizing enzymes in ligand-modulated transcription. Biochem Pharmacol 47:25-37.

Nebert, DW and WW Weber. 1990. Pharmacogenetics. In Principles of Drug Action. The Basis of Pharmacology, edited by WB Pratt and PW Taylor. New York: Churchill-Livingstone.

Nebert, DW and DR Nelson. 1991. P450 gene nomenclature based on evolution. In Methods of Enzymology. Cytochrome P450, edited by MR Waterman and EF Johnson. Orlando, Fla: Academic Press.

Nebert, DW and RA McKinnon. 1994. Cytochrome P450: Evolution and functional diversity. Prog Liv Dis 12:63-97.

Nebert, DW, M Adesnik, MJ Coon, RW Estabrook, FJ Gonzalez, FP Guengerich, IC Gunsalus, EF Johnson, B Kemper, W Levin, IR Phillips, R Sato, and MR Waterman. 1987. The P450 gene superfamily: Recommended nomenclature. DNA Cell Biol 6:1-11.

Nebert, DW, DR Nelson, MJ Coon, RW Estabrook, R Feyereisen, Y Fujii-Kuriyama, FJ Gonzalez, FP Guengerich, IC Gunsalas, EF Johnson, JC Loper, R Sato, MR Waterman, and DJ Waxman. 1991. The P450 superfamily: Update on new sequences, gene mapping, and recommended nomenclature. DNA Cell Biol 10:1-14.

Nebert, DW, DD Petersen, and A Puga. 1991. Human AH locus polymorphism and cancer: Inducibility of CYP1A1 and other genes by combustion products and dioxin. Pharmacogenetics 1:68-78.

Nebert, DW, A Puga, and V Vasiliou. 1993. Role of the Ah receptor and the dioxin-inducible [Ah] gene battery in toxicity, cancer, and signal transduction. Ann NY Acad Sci 685:624-640.

Nelson, DR, T Kamataki, DJ Waxman, FP Guengerich, RW Estabrook, R Feyereisen, FJ Gonzalez, MJ Coon, IC Gunsalus, O Gotoh, DW Nebert, and K Okuda. 1993. The P450 superfamily: Update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature. DNA Cell Biol 12:1-51.

Nicholson, DW, A All, NA Thornberry, JP Vaillancourt, CK Ding, M Gallant, Y Gareau, PR Griffin, M Labelle, YA Lazebnik, NA Munday, SM Raju, ME Smulson, TT Yamin, VL Yu, and DK Miller. 1995. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 376:37-43.

Nolan, RJ, WT Stott, and PG Watanabe. 1995. Toxicologic data in chemical safety evaluation. Chap. 2 in Patty’s Industrial Hygiene and Toxicology, edited by LJ Cralley, LV Cralley, and JS Bus. New York: John Wiley & Sons.

Nordberg, GF. 1976. Effect and Dose-Response Relationships of Toxic Metals. Amsterdam: Elsevier.

Office of Technology Assessment (OTA). 1985. Reproductive Hazards in the Workplace. Document No. OTA-BA-266. Washington, DC: Government Printing Office.

—. 1990. Neurotoxicity: Identifying and Controlling Poisons of the Nervous System. Document No. OTA-BA-436. Washington, DC: Government Printing Office.

Organization for Economic Cooperation and Development (OECD). 1993. US EPA/EC Joint Project On the Evaluation of (Quantitative) Structure Activity Relationships. Paris: OECD.

Park, CN and NC Hawkins. 1993. Technology review; an overview of cancer risk assessment. Toxicol Methods 3:63-86.

Pease, W, J Vandenberg, and WK Hooper. 1991. Comparing alternative approaches to establishing regulatory levels for reproductive toxicants: DBCP as a case study. Environ Health Persp 91:141-155.

Prpi<F"WP MultinationalA Roman"P6.5>ƒ<F255P255>-Maji<F"WP MultinationalA Roman"P6.5%0>ƒ<F255P255>, D, S Telišman, and S Kezi<F"WP MultinationalA Roman"P6.5%0>ƒ<F255P255>. 1984. In vitro study on lead and alcohol interaction and the inhibition of erythrocyte delta-aminolevulinic acid dehydratase in man. Scand J Work Environ Health 10:235-238.

Reitz, RH, RJ Nolan, and AM Schumann. 1987. Development of multispecies, multiroute pharmacokinetic models for methylene chloride and 1,1,1-trichloroethane. In Pharmacokinetics and Risk Assessment, Drinking Water and Health. Washington, DC: National Academy Press.

Roitt, I, J Brostoff, and D Male. 1989. Immunology. London: Gower Medical Publishing.

Sato, A. 1991. The effect of environmental factors on the pharmacokinetic behaviour of organic solvent vapours. Ann Occup Hyg 35:525-541.

Silbergeld, EK. 1990. Developing formal risk assessment methods for neurotoxicants: An evaluation of the state of the art. In Advances in Neurobehavioral Toxicology, edited by BL Johnson, WK Anger, A Durao, and C Xintaras. Chelsea, Mich.: Lewis.

Spencer, PS and HH Schaumberg. 1980. Experimental and Clinical Neurotoxicology. Baltimore: Williams & Wilkins.

Sweeney, AM, MR Meyer, JH Aarons, JL Mills, and RE LePorte. 1988. Evaluation of methods for the prospective identification of early fetal losses in environmental epidemiology studies. Am J Epidemiol 127:843-850.

Taylor, BA, HJ Heiniger, and H Meier. 1973. Genetic analysis of resistance to cadmium-induced testicular damage in mice. Proc Soc Exp Biol Med 143:629-633.

Telišman, S. 1995. Interactions of essential and/or toxic metals and metalloids regarding interindividual differences in susceptibility to various toxicants and chronic diseases in man. Arh rig rada toksikol 46:459-476.

Telišman, S, A Pinent, and D Prpi<F"WP MultinationalA Roman"P6.5J255%0>ƒ<F255P255J0>-Maji<F"WP MultinationalA Roman"P6.5J255%0>ƒ<F255P255J0>. 1993. Lead interference in zinc metabolism and the lead and zinc interaction in humans as a possible explanation of apparent individual susceptibility to lead. In Heavy Metals in the Environment, edited by RJ Allan and JO Nriagu. Edinburgh: CEP Consultants.

Telišman, S, D Prpi<F"WP MultinationalA Roman"P6.5%0>ƒ<F255P255>-Maji<F"WP MultinationalA Roman"P6.5%0>ƒ<F255P255>, and S Kezi<F"WP MultinationalA Roman"P6.5%0>ƒ<F255P255>. 1984. In vivo study on lead and alcohol interaction and the inhibition of erythrocyte delta-aminolevulinic acid dehydratase in man. Scand J Work Environ Health 10:239-244.

Tilson, HA and PA Cabe. 1978. Strategies for the assessment of neurobehavioral consequences of environmental factors. Environ Health Persp 26:287-299.

Trump, BF and AU Arstila. 1971. Cell injury and cell death. In Principles of Pathobiology, edited by MF LaVia and RB Hill Jr. New York: Oxford Univ. Press.

Trump, BF and IK Berezesky. 1992. The role of cytosolic Ca2<F"Symbol"P8>+<F255P255> in cell injury, necrosis and apoptosis. Curr Opin Cell Biol 4:227-232.

—. 1995. Calcium-mediated cell injury and cell death. FASEB J 9:219-228.

Trump, BF, IK Berezesky, and A Osornio-Vargas. 1981. Cell death and the disease process. The role of cell calcium. In Cell Death in Biology and Pathology, edited by ID Bowen and RA Lockshin. London: Chapman & Hall.

Vos, JG, M Younes and E Smith. 1995. Allergic Hyper-sensitivities Induced by Chemicals: Recommendations for Prevention Published on Behalf of the World Health Organization Regional Office for Europe. Boca Raton, FL: CRC Press.

Weber, WW. 1987. The Acetylator Genes and Drug Response. New York: Oxford Univ. Press.

World Health Organization (WHO). 1980. Recommended Health-Based Limits in Occupational Exposure to Heavy Metals. Technical Report Series, No. 647. Geneva: WHO.

—. 1986. Principles and Methods for the Assessment of Neurotoxicity Associated With Exposure to Chemicals. Environmental Health Criteria, No.60. Geneva: WHO.

—. 1987. Air Quality Guidelines for Europe. European Series, No. 23. Copenhagen: WHO Regional Publications.

—. 1989. Glossary of Terms On Chemical Safety for Use in IPCS Publications. Geneva: WHO.

—. 1993. The Derivation of Guidance Values for Health-Based Exposure Limits. Environmental Health Criteria, unedited draft. Geneva: WHO.

Wyllie, AH, JFR Kerr, and AR Currie. 1980. Cell death: The significance of apoptosis. Int Rev Cytol 68:251-306.

@REFS LABEL = Other relevant readings

Albert, RE. 1994. Carcinogen risk assessment in the US Environmental Protection Agency. Crit. Rev. Toxicol 24:75-85.

Alberts, B, D Bray, J Lewis, M Raff, K Roberts, and JD Watson. 1988. Molecular Biology of the Cell. New York: Garland Publishing.

Ariens, EJ. 1964. Molecular Pharmacology. Vol.1. New York: Academic Press.

Ariens, EJ, E Mutschler, and AM Simonis. 1978. Allgemeine Toxicologie [General Toxicology]. Stuttgart: Georg Thieme Verlag.

Ashby, J and RW Tennant. 1994. Prediction of rodent carcinogenicity for 44 chemicals: Results. Mutagenesis 9:7-15.

Ashford, NA, CJ Spadafor, DB Hattis, and CC Caldart. 1990. Monitoring the Worker for Exposure and Disease. Baltimore: Johns Hopkins Univ. Press.

Balabuha, NS and GE Fradkin. 1958. Nakoplenie radioaktivnih elementov v organizme I ih vivedenie [Accumulation of Radioactive Elements in the Organism and their Excretion]. Moskva: Medgiz.

Balls, M, J Bridges, and J Southee. 1991. Animals and Alternatives in Toxicology Present Status and Future Prospects. Nottingham, UK: The Fund for Replacement of Animals in Medical Experiments.

Berlin, A, J Dean, MH Draper, EMB Smith, and F Spreafico. 1987. Immunotoxicology. Dordrecht: Martinus Nijhoff.

Boyhous, A. 1974. Breathing. New York: Grune & Stratton.

Brandau, R and BH Lippold. 1982. Dermal and Transdermal Absorption. Stuttgart: Wissenschaftliche Verlagsgesellschaft.

Brusick, DJ. 1994. Methods for Genetic Risk Assessment. Boca Raton: Lewis Publishers.

Burrell, R. 1993. Human immune toxicity. Mol Aspects Med 14:1-81.

Castell, JV and MJ Gómez-Lechón. 1992. In Vitro Alternatives to Animal Pharmaco-Toxicology. Madrid, Spain: Farmaindustria.

Chapman, G. 1967. Body Fluids and their Functions. London: Edward Arnold.

Committee on Biological Markers of the National Research Council. 1987. Biological markers in environmental health research. Environ Health Persp 74:3-9.

Cralley, LJ, LV Cralley and JS Bus (eds.). 1978. Patty’s Industrial Hygiene and Toxicology. New York: Witey.

Dayan, AD, RF Hertel, E Heseltine, G Kazantis, EM Smith, and MT Van der Venne. 1990. Immunotoxicity of Metals and Immunotoxicology. New York: Plenum Press.

Djuric, D. 1987. Molecular-cellular Aspects of Occupational Exposure to Toxic Chemicals. In Part 1 Toxicokinetics. Geneva: WHO.

Duffus, JH. 1980. Environmental Toxicology. London: Edward Arnold.

ECOTOC. 1986. Structure-Activity Relationship in Toxicology and Ecotoxicology, Monograph No. 8. Brussels: ECOTOC.

Forth, W, D Henschler, and W Rummel. 1983. Pharmakologie und Toxikologie. Mannheim: Biblio- graphische Institut.

Frazier, JM. 1990. Scientific criteria for Validation of in VitroToxicity Tests. OECD Environmental Monograph, no. 36. Paris: OECD.

—. 1992. In Vitro Toxicity—Applications to Safety Evaluation. New York: Marcel Dekker.

Gad, SC. 1994. In Vitro Toxicology. New York: Raven Press.

Gadaskina, ID. 1970. Zhiroraya tkan I yadi [Fatty Tissues and Toxicants]. In Aktualnie Vaprosi promishlenoi toksikolgii [Actual Problems in Occupational Toxicology], edited by NV Lazarev. Leningrad: Ministry of Health RSFSR.

Gaylor, DW. 1983. The use of safety factors for controlling risk. J Toxicol Environ Health 11:329-336.

Gibson, GG, R Hubbard, and DV Parke. 1983. Immunotoxicology. London: Academic Press.

Goldberg, AM. 1983-1995. Alternatives in Toxicology. Vol. 1-12. New York: Mary Ann Liebert.

Grandjean, P. 1992. Individual susceptibility to toxicity. Toxicol Letters 64/65:43-51.

Hanke, J and JK Piotrowski. 1984. Biochemyczne podstawy toksikologii [Biochemical Basis of Toxicology]. Warsaw: PZWL.

Hatch, T and P Gross. 1954. Pulmonary Deposition and Retention of Inhaled Aerosols. New York: Academic Press.

Health Council of the Netherlands: Committee on the Evaluation of the Carcinogenicity of Chemical Substances. 1994. Risk assessment of carcinogenic chemicals in The Netherlands. Regul Toxicol Pharmacol 19:14-30.

Holland, WC, RL Klein, and AH Briggs. 1967. Molekulaere Pharmakologie.

Huff, JE. 1993. Chemicals and cancer in humans: First evidence in experimental animals. Environ Health Persp 100:201-210.

Klaassen, CD and DL Eaton. 1991. Principles of toxicology. Chap. 2 in Casarett and Doull’s Toxicology, edited by CD Klaassen, MO Amdur and J Doull. New York: Pergamon Press.

Kossover, EM. 1962. Molecular Biochemistry. New York: McGraw-Hill.

Kundiev, YI. 1975.Vssavanie pesticidov cherez kozsu I profilaktika otravlenii [Absorption of Pesticides Through Skin and Prevention of Intoxication]. Kiev: Zdorovia.

Kustov, VV, LA Tiunov, and JA Vasiljev. 1975. Komvinovanie deistvie promishlenih yadov [Combined Effects of Industrial Toxicants]. Moskva: Medicina.

Lauwerys, R. 1982. Toxicologie industrielle et intoxications professionelles. Paris: Masson.

Li, AP and RH Heflich. 1991. Genetic Toxicology. Boca Raton: CRC Press.

Loewey, AG and P Siekewitz. 1969. Cell Structure and Functions. New York: Holt, Reinhart and Winston.

Loomis, TA. 1976. Essentials of Toxicology. Philadelphia: Lea & Febiger.

Mendelsohn, ML and RJ Albertini. 1990. Mutation and the Environment, Parts A-E. New York: Wiley Liss.

Mettzler, DE. 1977. Biochemistry. New York: Academic Press.

Miller, K, JL Turk, and S Nicklin. 1992. Principles and Practice of Immunotoxicology. Oxford: Blackwells Scientific.

Ministry of International Trade and Industry. 1981. Handbook of Existing Chemical Substances. Tokyo: Chemical Daily Press.

—. 1987. Application for Approval of Chemicals by Chemical Substances Control Law. (In Japanese and in English). Tokyo: Kagaku Kogyo Nippo Press.

Montagna, W. 1956. The Structure and Function of Skin. New York: Academic Press.

Moolenaar, RJ. 1994. Carcinogen risk assessment: international comparison. Regul Toxicol Pharmacol 20:302-336.

National Research Council. 1989. Biological Markers in Reproductive Toxicity. Washington, DC: NAS Press.

Neuman, WG and M Neuman. 1958. The Chemical Dynamic of Bone Minerals. Chicago: The Univ. of Chicago Press.

Newcombe, DS, NR Rose, and JC Bloom. 1992. Clinical Immunotoxicology. New York: Raven Press.

Pacheco, H. 1973. La pharmacologie moleculaire. Paris: Presse Universitaire.

Piotrowski, JK. 1971. The Application of Metabolic and Excretory Kinetics to Problems of Industrial Toxicology. Washington, DC: US Department of Health, Education and Welfare.

—. 1983. Biochemical interactions of heavy metals: Methalothionein. In Health Effects of Combined Exposure to Chemicals. Copenhagen: WHO Regional Office for Europe.

Proceedings of the Arnold O. Beckman/IFCC Conference of Environmental Toxicology Biomarkers of Chemical Exposure. 1994. Clin Chem 40(7B).

Russell, WMS and RL Burch. 1959. The Principles of Humane Experimental Technique. London: Methuen & Co. Reprinted by Universities Federation for Animal Welfare,1993.

Rycroft, RJG, T Menné, PJ Frosch, and C Benezra. 1992. Textbook of Contact Dermatitis. Berlin: Springer-Verlag.

Schubert, J. 1951. Estimating radioelements in exposed individuals. Nucleonics 8:13-28.

Shelby, MD and E Zeiger. 1990. Activity of human carcinogens in the Salmonella and rodent bone-marrow cytogenetics tests. Mutat Res 234:257-261.

Stone, R. 1995. A molecular approach to cancer risk. Science 268:356-357.

Teisinger, J. 1984. Expositiontest in der Industrietoxikologie [Exposure Tests in Industrial Toxicology]. Berlin: VEB Verlag Volk und Gesundheit.

US Congress. 1990. Genetic Monitoring and Screening in the Workplace, OTA-BA-455. Washington, DC: US Government Printing Office.

VEB. 1981. Kleine Enzyklopaedie: Leben [Life]. Leipzig: VEB Bibliographische Institut.

Weil, E. 1975. Elements de toxicologie industrielle [Elements of Industrial Toxicology]. Paris: Masson et Cie.

World Health Organization (WHO). 1975. Methods Used in USSR for Establishing Safe Levels of Toxic Substances. Geneva: WHO.

1978. Principles and Methods for Evaluating the Toxicity of Chemicals, Part 1. Environmental Health Criteria, no.6. Geneva: WHO.

—. 1981. Combined Exposure to Chemicals, Interim Document no.11. Copenhagen: WHO Regional Office for Europe.

—. 1986. Principles of Toxicokinetic Studies. Environmental Health Criteria, no. 57. Geneva: WHO.

Yoftrey, JM and FC Courtice. 1956. Limphatics, Lymph and Lymphoid Tissue. Cambridge: Harvard Univ. Press.

Zakutinskiy, DI. 1959. Voprosi toksikologii radioaktivnih veshchestv [Problems of Toxicology of Radioactive Materials]. Moscow: Medgiz.

Zurlo, J, D Rudacille, and AM Goldberg. 1993. Animals and Alternatives in Testing: History, Science and Ethics. New York: Mary Ann Liebert.