Environmental Health Perspectives 105, Supplement 1, February 1997

12th Meeting of the Scientific Group on Methodologies for the Safety Evaluation of Chemicals: Susceptibility to Environmental Hazards

J. Carl Barrett,1 Harri Vainio,2 David Peakall,3 and Bernard D. Goldstein4


Part 7: Appendix and References


Analysis and Quality Assurance

Laboratory results are only useful if they are accurate and precise, and are reported in a responsible manner. Accuracy refers to the ability of the analyst to determine the exact quantity present in a sample. Precision refers to the ability to provide a consistent result (which may not necessarily be accurate, if for example, there is a failure in calibration). QA represents the sum total of activities that are required to produce reliable results (good precision and accuracy). In terms of laboratory analysis it includes setting data quality objectives on the one hand and evaluating quality control measures on the other. Stating a data quality objective consistent with the goals of the screening program or study is a necessary first step. Lack of resources or power sufficient to meet these objectives is grounds for not doing the study. Excessive power increases the cost.

Standard QC procedures have been well documented. Most published methodologies include QC procedures which must be individualized for each laboratory and each analytic instrument and procedure. Each laboratory must have a written QA/QC statement and protocol. These should be very detailed, including, for example, assurance that the deionized water is free of analytes in question, at least within the limits of detection required. Similarly, the purity of the solvents and reagents and the source of all standards should be specified.

Calibration procedures should use blanks and fresh standards within the range of anticipated concentrations. (One can only assume that a method yields linear results within the range of the calibration curve). The method detection limit should be specified for each analyte in each matrix (blood, urine, hair, etc). Field and method blanks should assure that there is no contamination at any point in the collection and analysis of samples. Spiked samples should assure that the technique can recover the analyte from the matrix. This allows one to document the percent recovery of the spike from the sample. Unless otherwise specified, it is customary to require that each analytic run produce a recovery between 85 and 115% of the actual spike. For some analytes it is difficult to achieve this level of accuracy on certain instruments, while for others tighter limits are routine. If recovery lies outside a certain range of values, then the entire run is rejected, and the stored samples are redigested and reanalyzed. Alternatively, some procedures allow the correction of the analytic results by the recovery percent. Thus if the recovery is only 80% of the spike, the results can be multiplied by 1.25 to correct for the deficiency. This approach is much less desirable and should be avoided, unless there is no further material available for analysis or unless the method repeatedly results in a similar recovery.

Each laboratory should participate regularly in a proficiency testing program involving the blind analysis of unknown samples provided by a reference laboratory. The results of such testing should be maintained with the QA/QC documents and should be available for inspection.

Challenges for Susceptibility Monitoring in Developing Nations

In many cases through international cooperation, developing nations are able to mount sophisticated screening programs for environmental as well as infectious agents. For example, the Mexican government, with the support of several international agencies such as United Nations Environmental Program, has been able to evaluate the exposure and possible effects of chemicals on human health for both acute and long-term exposures (Table A1). However, such programs can only touch the surface of the environmental pollution problems present throughout the world. Moreover, at the same time that industrialization is increasing in areas with minimal environmental regulation and enforcement, the developed nations are cutting back on funding for international cooperative programs.

Guidelines for the Implementation of Biomarker Studies

In any program the number of guidelines should be considered in implementing any screening program for biomarkers. These guidelines should include the following:

Overall Quality Planning
a) The economic resources available for the program must be identified.

b) The benefits of the program must be justified to assure adequate funding.

c) The intervention must be specified and funds identified in advance, if possible.

d) Where resources are not available for the "best" methodology, the use of alternative tests must be evaluated.

Quality Assurance
a) The screening protocol should include a statement of the data objectives and the required detection limits, the anticipated range of values, and the acceptable limits for precision and accuracy.

b) High quality laboratories should be identified.

c) All participating laboratories should have a written QA/QC document which should include documentation of participation in some Laboratory Proficiency program.

d) The protocol should allow for an internal QC program including blind replicates and confirmation of some percentage of the samples by an external reference laboratory.

e) Data quality evaluation should be completed prior to data analysis.

Standards for Collection of Samples
a) The population to be studied should be clearly identified and the people to be screened should be representative of the population of interest (minimize confounders).

b) All personnel should be selected carefully and should be conscientious and responsible.

c) All personnel (registrars, interviewers, phlebotomists, etc.) should be carefully trained and periodically evaluated.

d) Field sampling conditions should be made as ideal as possible. Use extreme precautions to avoid contaminating samples of blood, urine, etc. at the time of collection.

e) Care must be taken in the transportation of samples from the field to the central laboratory, particularly if samples require freezing or refrigeration.

f) All samples must be carefully and accurately labeled and a chain-of-custody form may be desirable for certain study situations.

Laboratory Standards and Practices
a) High-quality laboratory facilities are essential.

b) Where possible, a laboratory that is already functioning and of proven quality should be used.

c) Whether old or new, laboratories should be designed to eliminate both external and internal sources of contamination. This requires high standards of design and maintenance.

d) Laboratory equipment should be appropriate for the analyses being performed.

e) The appropriate preservation of samples is important, so facilities should have reliable refrigeration, preferably with a backup source of emergency electricity (gasoline generator).

f) All laboratory personnel should be trained; usually this will require training at an analytic center in a major city or outside the country. Training should embody the general principles of laboratory QA/QC and should also be relevant to the equipment available for use in the laboratory.

g) All results should be carefully checked for internal consistency. Deviant results should be repeated.

h) Laboratory supervision should be strict and consistent to assure high quality data.

Results
a) There should be adequate computing facilities and trained personnel for analysis of data.

b) All individual results should be treated as confidential and individuals should be informed of their own results with adequate information as medically appropriate.

c) The suppression of results for economic or political reasons is strongly discouraged.



table A1

References

1. International Programme on Chemical Safety. Biomarkers and Risk Assessment: Concepts and Principles. In: Environmental Health Criteria 155. Geneva:World Health Organization, 1993.

2. NAS. Biological Markers in Reproductive Toxicology. Report of the Oversight Committee. Washington:National Academy Press, 1989;15-35.

3. Nebert DW, Nelson DR. P450 gene nomenclature based on evolution. In: Cytochrome P450, Methods in Enzymology. Vol 206 (Waterman MR, Johnson EF, eds). Orlando, FL:Academic Press, 1991;3-11.

4. WHO. IPCS Environmental Health Criteria 155. Biomarkers and Risk Assessment: Concepts and Principles. Geneva:World Health Organization, 1993.

5. Jeyaratnam J. Occupational Health in Developing Countries. Oxford:Oxford University Press, 1982.

6. Mendelsohn ML, Peeters JP, Normandy MJ. Biomarkers and Occupational Health: Progress and Perspectives. Washington:Joseph Henry Press, 1995.

7. Lauwerys R, Buchet JP, Roels H. The relationship between cadmium exposure or body burden and the concentration of cadmium in blood and urine in man. Inter Arch Occup Environ Health 36:275-285 (1976).

8. Lauwerys RR. Objectives of biological monitoring in occupational health practice. In: Biological Monitoring and Surveillance of Workers Exposed to Chemicals (Aitio A, Riihimaki V, Vanio H, eds). New York:Hemisphere Publishing Company, 1984;3-6.

9. van Schooten FJ, Hillebrand MJX, van Leewen FE, van Zandwij N, Jansen HM, den Engelse L, Kriek E. Polycyclic aromatic hydrocarbon-DNA adducts in white blood cells from lung cancer patients: no correlation with adduct levels in lung. Carcinogenesis 13:987-993 (1992).

10. Zielhuis RL. Theoretical and practical consideration in biological monitoring. In: Biological Monitoring and Surveillance of Workers Exposed to Chemicals (Aitio A, Riihimaki V, Vanio H, eds). New York:Hemisphere Publishing, 1984;7-18.

11. Hemminki K. DNA adducts and mutations in occupational and environmental biomonitoring. Environ Health Perspect 105(Suppl 4):823-827 (1997).

12. Costa M, Zhitkovich A, Toniele P. DNA-protein cross-links in welders: molecular implications. Cancer Res 53:460-465 (1991).

13. Annest JL, Mahaffey KR. Blood lead levels for persons ages 6 months-74 years, in the United States, 1976-1980. DHHS 84-1683. Washington:U.S. Department of Health and Human Services.

14. Noren K. Studies of organochlorine contaminants in human milk. PhD Dissertation. Karolinska Institute, Stockholm, 1987.

15. Soskolne CL. Ethical, social, and legal issues surrounding studies of susceptible populations and individuals. Environ Health Perspect 105(Suppl 4):837-841 (1997).

16. Baselt R. Biological Monitoring Methods for Industrial Chemicals. Davis,CA:Biomedical Publications, 1988.

17. Hernberg. Lead. In: Biological Monitoring and Surveillance of Workers Exposed to Chemicals (Aitio A, Riihimaki V, Vainio H, eds). New York:Hemisphere Publishing, 1984.

18. Kosnett MJ. Factors influencing bone-lead concentration in a suburban community assessed by non-invasive K X-ray fluorescence. JAMA 271:197-203 (1994).

19. Romieu I, Carreon T, Lopez L, Palazuelos E, Rios C, Manuel Y, Hernandez-Avila M. Environmental urban lead exposure and blood lead levels in children of Mexico City. Environ Health Perspect 103(11):1036-1040 (1995).

20. Lindstedt G, Gottberg I, Holmgren B, Jonsson T, Karlsson G. Individual mercury exposure of chloralkalai workers and its relation to blood and urine mercury levels. Scand J Work Environ Health 5:59-69 (1979).

21. Giovanoli-Jakubczak T, Greenwood MR, Smith JC, Clarkson TW. Determination of total and inorganic mercury in hair by flameless atomic absorption, and of methylmercury by gas chromatography. Clin Chem 20:222-229 (1974).

22. Bernard A, Lauwerys R. Cadmium, NAG activity, and 2-microglobulin in the urine of cadmium pigment workers. Br J Ind Med 46:679-680 (1989).

23. Vartsky D, Ellis KJ, Chen NS, Cohn SH. A facility for in vivo measurement of kidney and liver cadmium by neutron capture prompt gamma-ray analysis. Phys Med Biol 20:88-95 (1975).

24. Jeyaratnam J. Acute pesticide poisoning: a major global health problem. World Health Stat Q 43:139-144 (1990).

25. WHO. Safe Use of Pesticides. 20th Report of the Expert Committee. WHO Technical Report Ser 513. Geneva:World Health Organization, 1973.

26. Anwar WA. Biomarkers of human exposure to pesticides. Environ Health Perspect 105(Suppl 4):801-806 (1997).

27. Coye MJ, Lowe JA, Maddy KJ. Biological monitoring of agricultural workers exposed to pesticides. II: Monitoring of intact pesticides and their metabolites. J Occup Med 28:628-636 (1986).

28. Wolfe HR, Durham WF, Armstrong JF. Urinary excretion of insecticide metabolites. Excretion of para-nitrophenol and DDA as indicators of exposure to parathion. Arch Environ Health 27:711-716 (1970).

29. Comer SW, Staiff DC, Armstrong JF, Wolfe HR. Exposure of workers to carbaryl. Bull Environ Contam Toxicol 13:385-391 (1975).

30. IARC. Occupational Exposures in Insecticide Application, and Some Pesticides In: IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol 53. Lyon:International Agency for Research on Cancer, 1991.

31. Walker CH. Biochemical responses as indicators of toxic effects of chemicals in ecosystems. Toxicol Lett 64-65:P527-533 (1992).

32. Shugart LR, Adams SM, Jiminez BD, Talmage SS, McCarthy JF. Biological markers to study exposure in animals and bioavailability of environmental contaminants. In: Biological Monitoring for Pesticide Exposure. Measurement, Estimation and Risk Reduction. ACS Symposium Ser 382 (Wang RGM, ed). Washington:American Chemical Society, 1989;85-97.

33. WHO/UNEP. Public Health Impact of Pesticides Used in Agriculture. Geneva:World Health Organization, 1990.

34. Ciesielski S, Loomis DP, Mims SR, Auer A. Pesticide exposures, cholinesterase depression, and symptoms among North Carolina migrant farmworkers. Am J Public Health 84(3):446-51 (1994).

35. Elovaara E, Heikkila P, Pyy L, Mutanen P, Riihiamki V. Significance of dermal and respiratory uptake in creosote workers: exposure to polycyclic aromatic hydrocarbons and urinary excretion of 1-hydroxypyrene. Occup Environ Med 52:192-203 (1995).

36. Øvrebø S, Fjeldstad PE, Grzybowska E, Kure EH, Chorazy M, Haugen A. Biological monitoring of polycyclic aromatic hydrocarbon exposure in a highly polluted area of Poland. Environ Health Perspect 103:838-843 (1995).

37. Jongeneelen F. Biological monitoring of occupational exposure to polycyclic aromatic hydrocarbons. Nijmegen, Netherlands:Scientific Publishers, 1987.

38. Lucas J, Tenjun T, Straume T, Pinkel D, Moore D, Litt M, Gray J. Rapid determination of human chromosome translocation frequency using a pair of chromosome-specific DNA problems. Int J Radiat Biol 56:35-44 (1989).

39. Kelsey KT, Wiencke JK, Liber HL. Biomarkers to detect radiation exposures. In: Biomarkers and Occupational Health: Progress and Perspectives (Mendelsohn ML, Peeters JP, Normandy M, eds). Washington:Joseph Henry Press, 1995;215-225.

40. Evans HJ Human peripheral blood lymphocytes for the analysis of chromosome aberrations in mutagen tests. In: Handbook of Mutagenicity Test Procedures, 2nd ed (Kilbey BJ, Legator M, Nichols W, Ramel C, eds). Amsterdam:Elsevier, 1984;405-427.

41. Rosin MP. The use of the micronucleus test on exfoliated cells to identify anti-clastogenic action in humans: a biological marker for the efficacy of chemotherapeutic agents. Mutat Res 267:265-276 (1992).

42. Anwar WA, Rosin MP. Reduction in chromosomal damage in schistosomiasis patients after treatment with praziquantel. Mutat Res 298:179-185 (1993).

43. Lähdetie J. Occupation- and exposure-related studies on human sperm. J Occup Med 37:922-930 (1995).

44. Hagmar L, Brøgger A, Hansteen I-L, Heim S, Hogstedt B, Knudsen L, Lambert B, Linnainmaa K, Nordenson I, Reuterwall C et al. Cancer risk in humans predicted by increased levels of chromosomal aberrations in lymphocytes: Nordic Study Group on the Health Risks of Chromosome Damage. Cancer Res 54:2919-2922 (1994).

45. Bonassi S, Abbondandolo A, Camurri L, Dal Prá L, De Ferrari M, Degrassi F, Forni A, Lamberti L, Lando C, Padovani P et al. Are chromosome aberrations in circulating lymphocytes predictive of future cancer onset in humans? Preliminary results of an Italian Cohort Study. Cancer Genet Cytogenet 79:133-135 (1995).

46. Norppa H. Cytogenetic markers of susceptibility: influence of genetic polymorphisms of xenobiotic-metabolizing enzymes. Environ Health Perspect 105(Suppl 4):829-835 (1997).

47. Wiencke JK, Pemble S, Ketterer B, Kelsey KT. Gene deletion of glutathione S-transferase: correlation with induced genetic damage and potential role in endogenous mutagenesis. Cancer Epidemiol Biomarkers Prev 4:253-259 (1995).

48. Lucas JN, Tenjin T, Straume T, Pinkel D, Moore D, Litt M, Gray, JW. Rapid human chromosome aberration analysis using fluorescence in situ hybridization. Int J Radiat Biol 56:35-44 (1989).

49. Rupa DS, Hasegawa L, Eastmond DA. Detection of chromosomal breakage in the 1cen-1q12 region of interphase human lymphocytes using multicolor fluorescence in situ hybridization with tandem DNA probes. Cancer Res 55:640-645 (1995).

50. Smith MT, Rothman N, Zhang L, Wang Y, Hayes RB, Yin SN. Molecular cytogenetics of humans exposed to benzene. Fundam Appl Toxicol 30 (No 1, part 1; Suppl):178 (1996).

51. Lipkowitz S, Garry VF, Kirsch IR. Interlocus V-J recombination measures genomic instability in agriculture workers at risk for lymphoid malignancies. Proc Natl Acad Sci USA 89:5301-5305 (1992).

52. Bell DA, Liu Y, Cortopassi GA. Occurrence of bcl-2 oncogene translocation with increased frequency in the peripheral blood of heavy smokers. J Natl Cancer Inst 87:223-224 (1995).

53. Wiencke JK, Wrensch MR, Miike R, Petrakis NL. Individual susceptibility to induced chromosome damage and its implications for detecting genotoxic exposures in human populations. Cancer Res 51:5266-5269 (1991b).

54. Cervenka J, Hirsch BA. Cytogenetic differentiation of Fanconi anemia, "idiopathic" aplastic anemia, and Fanconi anemia heterozygotes. Am J Med Genet 15:211-223 (1983).

55. Wiencke JK, Christiani DC, Kelsey KT. Bimodal distribution of sensitivity to SCE induction by diepoxybutane in human lymphocytes. I: Correlation with chromosomal aberrations. Mutat Res 248:17-26 (1991a).

56. Sorsa M, Osterman-Golkar S, Peltonen K, Saarikoski S, Srám R. Assessment of exposure to butadiene in the process industry. Toxicology 113:77-83 (1996).

57. Norppa H, Hirvonen A, Järventaus H, Uusküla M, Tasa G, Ojajärvi A, Sorsa M. Role of GSTT1 and GSTM1 genotypes in determining individual sensitivity to sister chromatid exchange induction by diepoxybutane in cultured human lymphocytes. Carcinogenesis 16:1261-1264 (1995).

58. Tucker JD, Auletta A., Cimino MC, Dearfield KL, Jacobson-Kram D, Tice RT, Carrano AV. Sister-chromatid exchange: second report of the Gene-Tox program. Mutat Res 297:101-180 (1993).

59. Oikawa A, Sakai S, Horaguchi K, Tohda H. Sensitivities of peripheral lymphocytes from healthy humans to induction of sister chromatid exchanges by chemicals. Cancer Res 43:439-442 (1983).

60. Kelsey KT, Christiani DC, Wiencke JK. Bimodal distribution of sensitivity to SCE induction by diepoxybutane in human lymphocytes. II. Relationship to baseline SCE frequency. Mutat Res 248:27-33 (1991).

61. Hallier E, Langhof T, Dannappel D, Leutbecher M, Schröder K, Goergens HW, Müller A, Bolt HM. Polymorphism of glutathione conjugation of methyl bromide, ethylene oxide and dichloromethane in human blood: influence on the induction of sister chromatid exchanges (SCE) in lymphocytes. Arch Toxicol 67:173-178 (1993).

62. Kelsey KT, Wiencke JK, Ward J, Bechtold W, Fajen J. Sister chromatid exchanges, glutathione S-transferase deletion and cytogenetic sensitivity to diepoxybutane in lymphocytes from butadiene monomer production workers. Mutat Res 335:267-273 (1995).

63. Uusküla M, Järventaus H, Hirvonen A, Sorsa M, Norppa H. Influence of GSTM1 genotype on sister chromatid exchange induction by styrene-7,8-oxide and 1,2-epoxy-3-butene in cultured human lymphocytes. Carcinogenesis 16:947-950 (1995).

64. Landi S, Ponzanelli I, Hirvonen A, Norppa H, Barale R. Repeated analysis of sister chromatid exchange induction by diepoxybutane in cultured human lymphocytes: effect of glutathione S-transferase T1 and M1 genotype. Mutat Res 351:79-85 (1996).

65. Norppa H, Pelin K, Järventaus H, Ollikainen T, Knudsen L, Okkels H, Scarpato R, Migliore L, Hirvonen A. Polymorphisms of xenobiotic metabolizing enzymes: influence on cytogenetic parameters in vitro and in vivo. In: The 4th Nordic Toxicology Meeting, 27-31 March 1996, Storlien, Sweden. Abstract.

66. Pelin K, Hirvonen A, Norppa, H. Influence of erythrocyte glutathione S-transferase T1 on sister chromatid exchanges induced by diepoxybutane in cultured human lymphocytes. Mutagenesis 11:213-215 (1996).

67. Cheng T-J, Christiani DC, Xu X, Wain JC, Wiencke JK, Kelsey KT. Glutathione S-transferase genotype, diet, and smoking as determinants of sister chromatid exchange frequency in lymphocytes. Cancer Epidemiol Biomarkers Prev 4:535-542 (1995).

68. van Poppel G, de Vogel N, van Balderen J, Kok FJ. Increased cytogenetic damage in smokers deficient in glutathione S-transferase isozyme. Carcinogenesis 13:303-305 (1992).

69. Morimoto K, Takeshita T, Imayyoshi S, Mure K, Inoue C. Low Km aldehyde dehydrogenase (ALDH2) polymorphism and chromosome alterations in alcohol drinkers. In: 2nd International Conference on Environmental Mutagens in Human Populations, 20-25 August 1995, Prague. Abstract.

70. Heddle JA, Cimino MC, Hayashi M, Romagna F, Shelby MD, Tucker JD, Vanparys Ph, MacGregor JT. Micronuclei as an index of cytogenetic damage: past, present, and future. Environ Mol Mutagen 18:277-291 (1991).

71. Fenech M, Morley AA. Measurement of micronuclei in lymphocytes. Mutat Res 147:29-36 (1985).

72. Thomson EJ, Perry PE. The identification of micronucleated chromosomes: a possible assay for aneuploidy. Mutagenesis 7:407-410 (1988).

73. Norppa H, Renzi L, Lindholm C. Detection of whole chromosomes in micronuclei of cytokinesis-blocked human lymphocytes by antikinetochore staining and in situ hybridization. Mutagenesis 8:519-525 (1993).

74. Norppa H, Luomahaara S, Heikanen H, Roth S, Sorsa M, Renzi L, Lindholm C. Micronucleus assay in lymphocytes as a tool to biomonitor human exposure to aneuploidogens and clastogens. Environ Health Perspect 101(Suppl 3):139-143 (1993).

75. Richard F, Muleris M, Dutrillaux B. The frequency of micronuclei with X chromosomes increases with age in human females. Mutat Res 316:1-7 (1994).

76. Catalán J, Autio K, Wessman M, Lindholm C, Knuutila S, Sorsa M, Norppa H. Age-associated micronuclei containing centromeres and the X chromosome in lymphocytes of women. Cytogenet Cell Genet 68:11-16 (1995).

77. Nath J, Tucker JD, Hando JC. Y chromosome aneuploidy, micronuclei, kinetochores and aging men. Chromosoma 103:725-731 (1995).

78. Ballarin G, Sarto F, Giacomelli C, Bartolucci GB, Clonofero E. Micronucleated cells in nasal mucosa of formaldehyde-exposed workers. Mutat Res 280:1-7 (1992).

79. McGinniss MJ, Nicklas JA, Albertini RA. Molecular analyses of in vivo HPRT mutations in human T-lymphocytes. IV: Studies in newborns. Environ Mol Mutagen 14:229-237 (1989).

80. Cole J, Skopek RT. Somatic mutation frequency, mutation rates and mutational spectra in the human population. Mutat Res 304:33-105 (1994).

81. Perera FP, Dickey C, Santella R, O'Neill JPO, Albertini RJ, Ottman R, Tsai WY, Mooney LA, Savela K, Hemminki K. Carcinogen-DNA adducts and gene mutation in foundry workers with low-level exposure to polycyclic aromatic hydrocarbons. Carcinogenesis 15:2905-2910 (1994).

82. Perera FP, Tang DL, O'Neill JP, Bigbee WL, Albertini RJ, Santella R, Ottman R, Tsai, WY, Dickey C, Mooney LA. HPRT and glycophorin A mutations in foundry workers: relationship to PAH exposure and to PAH-DNA adducts. Carcinogenesis 14:969-973 (1993).

83. Hou S-M, Lambert B, Hemminki K. Relationship between HPRT mutant frequency, aromatic DNA adducts and genotypes for GSTM1 and NAT2 in bus maintenance workers. Carcinogenesis 16:1913-1917 (1995).

84. Langlois RJ, Bigbee WL, Kyoizumi SK, Nakamura N, Bean MA, Akiyama M, Jensen RW. Evidence for increased somatic cell mutations at the glycophorin A locus in atomic bomb survivors. Science 236:445-448 (1987).

85. Langlois RG, Nisbet BA, Bigbee WL, Ridinger DN, Jensen RH. An improved flow cytometric assay for somatic mutations at the glycophorin A locus in humans. Cytometry 11:513-521 (1990).

86. Grant SG, Bigbee WL. in vivo somatic mutation and segregation at the human glycophorin A (GPA) locus: phenotypic variation encompassing both gene-specific and chromosomal mechanisms. Mutat Res 288:163-172 (1993).

87. Bigbee WL, Grant SG, Langlois RC, Jensen RH, Anttila A, Pfäffli P, Pekari K, Norppa H. Glycophorin A (GPA) somatic cell mutation frequencies in Finnish reinforced plastics workers exposed to styrene. Cancer Epidemiol Biomarkers Prev 5:801-810 (1996).

88. Langlois AM, Lockhart AM, Watson MA, Thopson CL, Bell DA. Evidence that GSTT1 affects the induction of glycophorin A variant cells in smokers. Environ Mol Mutagen 27(Suppl 27):39 (1996).

89. Bos JL, Verlaan-de Vries M, Jansen AM, Veeneman GH, van Boom JH, van der Eb AJ. Three different mutations in codon 61 of the human N-ras gene detected by synthetic oligonucleotide hybridization. Nucleic Acids Res 12:9155-9163 (1984).

90. Balmain A, Brown K. Oncogene activation in chemical carcinogenesis. Adv Cancer Res 51:147-182 (1988).

91. Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 Mutations in human cancers. Science 253:49-53 (1991).

92. Harris CC, Hollstein M. Clinical implications of the p53 tumor-suppressor gene. N Engl J Med 329:1318-1327 (1993).

93. Puisieux A, Lim S, Groopman J, Ozturk M. Selective targeting of the p53 gene mutational hotspots in human cancers by etiologically defined carcinogens. Cancer Res 51:6185-6189 (1991).

94. Biggs PJ, Warren W, Venitt S, Stratton MR. Does a genotoxic carcinogen contribute to human breast cancer? The value of mutational spectra in unraveling the aetiology of cancer. Mutagenesis 8:275-283 (1993).

95. Aguilar F, Hussain SP, Cerutti P. Aflatoxin B1 induces the transversion of GT in codon 249 of the p53 tumor suppressor gene in human hepatocytes. Proc Natl Acad Sci USA 90:8586-8590 (1993).

96. Aguilar F, Harris CC, Sun T, Hollstein M, Cerutti P. Geographical variation of p53 mutational profile in nonmalignant human liver. Science 264:1317-1319 (1994).

97. Almstad P, Hussain SP, Cerutti P. Ultraviolet B light-induced mutagenesis of p53 hotspot codon 248 and 249 in human skin fibroblasts. Mol Carcinog 10:181-188 (1994).

98. Esteve A, Srlie T, Martel-Planche G, Hollstein M, Kusters I, Lewalter J, Vineis P, Stephan-Odenthal, Montesano R. Screening for p53 gene mutations in archived tumors of workers occupationally exposed to carcinogens: examples from analysis of bladder tumors. J Occup Environ Med 37:59-68 (1995).

99. Husgafvel-Pursiainen K, Ridanpää M, Anttila S, Vainio H. p53 and ras gene mutations in lung cancer: implications for smoking and occupational exposures. J Occup Environ Med 37:69- 76 (1995).

100. Bartsch H, Hollstein M, Mustonen R, Schmidt J, Spiethoff A, Wesch H, Wiethege T, Müller K-M. Screening for putative radon-specific p53 mutation hotspot in German uranium miners. Lancet 346:8967 (1995).

101. Takeshima Y, Seyama T, Bennett WP, Akiyama M, Tokuoka S, Inai K, Mabuchi K, Land CE, Harris CC. p53 mutations in lung cancers from non-smoking atomic-bomb survivors. Lancet 342:1520-1521 (1993).

102. Brennan JA, Boyle JO, Koch WM, Goodman SN, Hruban RH, Eby YJ, Couch MJ, Forastiere AA, Sidransky D. Association between cigarette smoking and mutation of the p53 gene in squamous-cell carcinoma of the head and neck. N Engl J Med 332:712-717 (1995).

103. Ryberg D, Hewr A, Phillips DH, Haugen A. Different susceptibility to smoking-induced DNA damage among male and female lung cancer patients. Cancer Res 54:5801-5803 (1994).

104. Rydberg D, Kure E, Lystad S, Skaug V, Stangeland L, Mercy I, Børresen A-L, Haugen A. p53 Mutations in lung tumors: relationship to putative susceptibility markers for cancer. Cancer Res 54:1551-1555 (1994).

105. Kawajiri K, Eguch H, Nakachi K, Sekiya T, Yamamoto M. Association of CYP1A1 germ line polymorphisms with mutations of the p53 gene in lung cancer. Cancer Res 56:72-76 (1996).

106. Myers RM, Larin Z, Maniatis T. Detection of single base substitutions by ribonuclease cleavage at mismatches in RNA:DNA duplexes. Science 230:1242-1246 (1985).

107. Smooker PM, Cotton RGH. The use of chemical reagents in the detection of DNA mutations. Mutat Res 288:65-77 (1993).

108. Orita M, Iwahana H, Kanazawa H, Hayashi K, Sekiya T. Detection of polymorphisms of human DNA by gel electrophoresis as single strand conformation polymorphisms. Proc Natl Acad Sci USA 86:2766-2770 (1989).

109. Sekiya T. Detection of mutant sequences by single-strand conformation polymorphism analysis. Mutat Res 288:79-83 (1993).

110. Fan E, Levin DB, Glickman BW, Logan DM. Limitations in the use of SSCP analysis. Mutat Res 288:85-92 (1993).

111. Fischer SG, Lerman LS. DNA fragments differing by single base-pair substitutions are separated in denaturing gradient gels: correspondence with melting theory. Proc Natl Acad Sci USA 80:1579-1583 (1983).

112. Cariello NF, Skopek TR. Mutational analysis using denaturing gradient gel electrophoresis and PCR. Mutat Res 288:103-112 (1993).

113. Hovig E, Smith-Srensen B, Brøgger A, Børresen A-L. Constant denaturant gel electrophoresis, a modification of denaturing gradient gel electrophoresis, in mutation detection. Mutat Res 262:63-71 (1991).

114. Khrapko K, Hanekamp JS, Thilly WG, Belenkii A, Foret F, Karger BL. Constant denaturing capillary electrophoresis (CDCE): a high resolution approach to mutational analysis. Nucleic Acid Res 22:364-369 (1994).

115. Bos JL. ras oncogenes in human cancer: a review. Cancer Res 49:4682-4689 (1989).

116. Pourzand C, Cerutti P. Genotypic mutation analysis by RFLP/PCR. Mutat Res 288:113-121 (1993).

117. Cerutti P, Hussain P, Pourzand C, Aguilar F. Mutagenesis of the H-ras protooncogene and the p53 tumor suppressor gene. Cancer Res 54:1934s-1938s (1994).

118. Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA 74:5463-5467 (1977).

119. Pease AC, Solas D, Sullivan EJ, Cronin MT, Holmes CP, Fodor SPA. Light-generated oligonucleotide arrays for rapid DNA sequence analysis. Proc Natl Acad Sci USA 91:5022-5026 (1994).

120. Hultman T, Ståhl S, Hornes E, Uhlén M. Direct solid phase sequencing of genomic and plasmid using magnetic beads as solid support. Nucleic Acids Res 17:4937-4946 (1989).

121. Syvänen A-C, Söderlund H, Laaksonen E, Bengtström M, Turunen M, Palotie A. N-ras gene mutations in acute myeloid leukemia: accurate detection by solid-phase minisequencing. Int J Cancer 50:713-718 (1992).

122. Funa K, Steinholtz L, Nou E, Bergh J. Increased expression of N-myc in human small cell lung cancer biopsies predicts lack of response to chemotherapy and poor prognosis. Am J Clin Pathol 88:216-220 (1987).

123. Limper AH, Broekelmann TJ, Colby TV, Malizia G, McDonald JA. Analysis of local mRNA expression for extracellular matrix proteins and growth factors using in situ hybridization in fibroproliferative lung disorders. Chest 99:555-565 (1991).

124. Koutselini H, Kappatou G, Yiagnisis M, Field JK, Spandidos DA. Immunocytochemical study of ras oncoprotein in cytologic specimens of primary lung tumours. Anticancer Res 10:597-604 (1990).

125. Gallick GE, Kurzrock R, Kloetzer WS, Arlinghaus RB, Gutterman JU. Expression of p21 ras in fresh primary and metastatic human colorectal tumors. Proc Natl Acad Sci USA 82:1795-1799 (1985).

126. Kurzrock R, Gallick GE, Gutterman JU. Differential expression of p21 ras gene products among histological subtypes of fresh primary human lung tumors. Cancer Res 46:1530-1534 (1986).

127. Ruckle HC, Klee GG, Desterling JE. Prostate-specific antigen: critical issues for the practicing physician. Mayo Clin Proc 69:59-68 (1994).

128. Ruckle HC, Klee GG, Oesterling JE. Prostate-specific antigen: concepts for staging prostate cancer and monitoring response to the copy. Mayo Clin Proc 69:69-79 (1994).

129. Brandt-Rauf PW. Biomarkers of gene expression--growth factors and oncoproteins. Environ Health Perspect 105(Suppl 4):807-816 (1997).

130. Ashby J, Anwar W, Au WW, Massoud A, Gentile JM. Genetic toxicology in developing countries: comments and recommendations. Environ Health Perspect (Suppl 3):335-338 (1993).

131. Anwar WA. Cytogenetic monitoring of human populations at risk in Egypt: role of cytogenetic data in cancer risk assessment. Environ Health Perspect 96:91-95 (1991).

132. Burchell B, Coughtrie MWH. Genetic and environmental factors associated with variation of human xenobiotic glucuronidation and sulfation. Environ Health Perspect 105(Suppl 4):739-747 (1997).

133. Goldstein BD, Amoruso MA, Witz G. Erythrocyte glucose-6-phosphate dehydrogenase deficiency does not pose an increased risk for black Americans exposed to oxidant gases in the workplace or general environment. Toxicol Ind Health 1:75-80 (1985).

134. Ramel C. Mini- and microsatellites. Environ Health Perspect 105(Suppl 4):781-789 (1997).

135. Alvan G, Bechtel P, Iselius L, Gundert-Remy U. Hydroxylation polymorphisms of debrisoquine and mephenytoin in European populations. Eur J Pharmacol 39:533-537 (1990).

136. Daly AK, Cholerton S, Gregory W, Idle JR. Metabolic polymorphisms. Pharmacol Ther 57:129-160 (1993).

137. Horn EP, Tucker MA, Lambert G, Silverman D, Zametkin D, Sinha R, Hartege T, Landi MT, Caporaso NE. A study of gender-based cytochrome P4501A2 variability: a possible mechanism for the male excess of bladder cancer. Cancer Epidemiol Biomarkers Prev 4(5):529-33 (1995).

138. Pelkonen O, Raunio H. Metabolic activation of toxins. Tissue-specific expression and metabolism in target organs. Environ Health Perspect 105(Suppl 4):767-774 (1997).

139. Vanden Heuvel JP, Clark GC, Thompson CL, McCoy Z, Miller CR, Lucier GW, Bell DA. CYP1A1 mRNA levels as a human exposure biomarker: use of quantitative polymerase chain reaction to measure CYP1A1 expression in human peripheral blood lymphocytes. Carcinogenesis 14:2003-2006 (1993).

140. Gonzalez FJ, Skoda R, Kimura S, Umeno M, Zanger UM, Nebert DW, Gelboin HV, Hardwick JP, Meyer UA. Characterization of the common genetic defect in humans deficient in debrisoquine metabolism. Nature 331:442-446 (1988).

141. Kagimoto M, Heim M, Kagimoto K, Zeugin T, Meyer UA. Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolizers of debrisoquine. J Biol Chem 265:17209-17214 (1990).

142. Yamano S, Tatsuno J, Gonzales FJ. The CYP2A6 gene product catalyzes coumarin 7-hydroxylation in human liver microsomes Biochemistry 29:1322-1329 (1990).

143. Hayashi SI, Watanabe J, Kawajiri K. Genetic polymorphisms in the 5´-flanking region change transcriptional regulation of the human cytochrome P450IIE1 gene. J Biochem 110:559-565 (1991).

144. Ambrosone CB, Freudenheim JL, Graham S, Marshall JR, Vena JR, Brasure JR, Laughlin R, Nemoto T, Michalek AM, Harrington A et al. Cytochrome P450 1A1 and glutathione S-transferase (M1) genetic polymorphisms and postmenopausal breast cancer risk. Cancer Res 55:3483-3485 (1995).

145. Oyama T, Mitsudomi T, Kawamoto T, Ogami A, Osaki T, Kodama Y, Yasumoto K. Detection of CYP1A1 gene polymorphism using designed RFLP and distributions of CYP1A1 genotypes in Japanese. Int Arch Occup Environ Health 67:253-256 (1995).

146. Hayashi SI, Watanabe J, Nakachi K, Kawajiri K. Genetic linkage of lung cancer-associated MspI polymorphisms with amino acid replacement in the heme binding region of the human cytochrome P4501A1 gene. J Biochem 110:407-411 (1991b).

147. Zimmerman LJ, Fuscoe JC. Direct DNA sequencing of PCR products. Environ Mol Mutagen 18:274-276 (1991).

148. Birdsong WH, Lash AA, Thayer S, Kumekawa E, Becker CE. The validity of study group assignments based on occupational histories obtained from questionnaires. J Occup Med 34:940-945 (1992).

149. Hemminki K, Lindbohm M-L, Kyyrönen P. Validity aspects of exposure and outcome data in reproductive studies. J Occup Environ Med 37:903-907 (1995).

150. London SJ, Daly AK, Thomas CD, Caporaso NE, Idle JR. Methodological issues in interpretation of studies of the CYP2D6 genotype in relation to lung cancer risk. Pharmacogenetics 4:107-108 (1994).

151. Hosmer DW, Lemeshow S. Applied Logistic Regression. New York:John Wiley & Sons, 1984.

152. Tasa G, Uuskula M, Hirvonen A, Mikkelsaar A-V. Optimization of PCR to yield successful amplification from heparin-contaminated DNA. Methods Mol Cell Biol 5:122-124 (1995).

153. Liu Y-H, Bai J, Zhu Y, Liang X, Siemieniak D, Venta P, Lubman DM. Rapid screening of genetic polymorphisms using buccal cell DNA with detection by matrix-assisted laser desorption ionization mass spectrometry. Rapid Commun Mass Spectrom 9:735-743 (1995).

154. Hirvonen A. Combinations of susceptible genotypes and individual responses to toxicants. Environ Health Perspect 105(Suppl 4):755-758 (1997).

155. Landi MT, Bertazzi PA, Shields PG, Clark G, Lucier GW, Garte SJ, Cosma G, Caporaso NE. Association between CYP1A1 genotype, mRNA expression and enzymatic activity in humans. Pharmacogenetics 4:242-246 (1994).

156. Broly F, Marez D, Sabbagh N, Legrand M, Millecamps S, Lo Guidice J-M, Boone P, Meyer UA. An efficient strategy for detection of known and new mutations of the CYP2D6 gene using single strand conformation polymorphism analysis. Pharmacogenetics 5:373-384 (1995).

157. Bell D, Taylor JA, Paulson D, Robertson CN, Mohler JL, Lucier GW. Genetic risk and carcinogen exposure: a common inherited defect of the carcinogen metabolism gene glutathione S-transferase M1 (GSTM1) that increases susceptibility to bladder cancer. J Natl Cancer Inst 85:1159-1164 (1993).

158. Seidegård J, Vorachek WR, Pero RW, Pearson WR. Hereditary differences in the expression of the human glutathione transferase active on trans-stilbene oxide are due to a gene deletion. Proc Natl Acad Sci USA 85:7293-7297 (1988).

159. Steen VM, Andreassen OA, Daly AK, Tefre T, Borresen A-L, Idle JR, Guldbrandsen A-K. Detection of poor metabolizer-associated CYP2D6(D) gene deletion allele by long-PCR technology. Pharmacogenetics 5:215-223 (1995).

160. Johansson I, Lundqvist E, Bertilsson L, Dahl M-L, Sjöqvist F, Ingelman-Sundberg M. Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultrarapid metabolism of debrisoquine. Proc Natl Acad Sci USA 90:11825-11829 (1993).

161. Vanden Heuvel JP, Clark GC, Kohn MC, Tritscher AM, Greenlee WF, Lucier GW, Bell DA. Dioxin-responsive genes: examination of dose-response relationships using quantitative reverse transcriptase-polymersase chain reaction. Cancer Res 54(1):62-8 (1994).

162. Rayemaekers L. A commentary on the practical applications of competitive PCR. Genome Res 5:91-94 (1995).

163. Kwok S, Higuchi R. Avoid false positives with PCR. Nature 339:237-238 (1989).

164. Syvänen A-C, Sajantila A, Lukka A. Identification of individuals by analysis of biallelic DNA markers, using PCR and solid-phase minisequencing. Am J Hum Genet 52:46-59 (1993).

165. McCarthy JF, Shugart LR. Biological markers of environmental contamination. In: Biomarkers of Environmental Contamination (McCarthy JF, Shugart LR, eds). Boca Raton, FL:Lewis Publishers, 1990;3-14.

166. Huggett RJ, Kimerle RA, Mehrle PM Jr, Bergman HL, eds. Biomarkers. Biochemical, Physiological, and Histological Markers of Anthropogenic Stress. Boca Raton, FL:Lewis Publishers, 1992.

167. Peakall, DB. Animal Biomarkers as Pollution Indicators. London:Chapman & Hall, 1992.

168. Varanasi U, Reichert WL, Stein JE. 32P-Postlabeling analysis of DNA adducts in liver of wild English sole (Parophys vetulus) and winter flounder (Pseudopleuronectes americanus). Cancer Res 49:1171-1177 (1989).

169. Stein JE, Reichert WL, Nishimoto M, Varanasi U. Overview of studies on liver carcinogenesis in English sole from Puget Sound; evidence for a xenobiotic chemical etiology. II. Biochemical studies. Sci Total Environ 94:51-69 (1990).

170. Shugart LR. Detection and quantitation of benzo(a)pyrene-DNA adducts in brain and liver tissues of beluga whales (Delphinapterus leucas) from the St. Lawrence and Mackenzie estuaries. In: Proceedings of the International Forum for the Future of the Beluga. 1990;219-223.

171. Kurelec B. The genotoxic disease syndrome. Marine Environ Res 35:341-348 (1993).

172. Shugart LR, McCarthy JF, Jimenez BD, Daniels J. Analysis of adduct formation in the bluegill sunfish (Lepomis macrochirus) between benzo[a]pyrene and DNA of the liver and hemoglobin of the erythrocyte. Aquatic Toxicol 9:319-325 (1987).

173. Kurelec B, Gupta RC. Biomonitoring of aquatic systems. In: Postlabelling Methods for Detection of DNA Adducts (Phillips, DH, Castegnaro, M, Bartsch H, eds). Lyon:International Agency on Research on Cancer, 1993; 365-372.

174. Petersen LB-M, Petersen RC. Anomalies in hydropsychid capture nets from polluted streams. Freshwater Biol 13:185-191 (1983).

175. Peterle TJ. Wildlife Toxicology. New York:Van Nostrand Reinhold, 1991.

176. Adkisson PL, Niles GA, Walker JK, Bird LS Scott HB. Controlling cotton's insect pests: a new system. Science 216:19-22 (1982).

177. Kurelec, B. The multixenobiotic resistance mechanism in aquatic organisms. Crit Rev Toxicol 22:23-43 (1992).

178. Kurelec B. A new type of hazardous chemical: the chemosensitizers of multixenobiotic resistance. Environ Health Perspect 105(Suppl 4):855-860 (1997).

179. Kurelec B, Luci´c D, Piv´cevi´c B, Kr´ca S. Induction and reversion of multixenobiotic resistance in the marine snail Monodonta turbinata. Marine Biol 123:305-312 (1995).

180. Minier C, Akcha F, Galgani F. P-glycoprotein expression in Crassostrea gigas and Mytilus edulis in polluted seawater. Comp Biochem Physiol B Comp Biochem 106B:1029-1036 (1993).

181. Waldmann P, Piv´cevi´c B, Mueller WEG, Zahn RK, Kurelec B. Increased genotoxicity of aminoanthracene by modulators of multixenobiotic resistance mechanism: studies with the fresh water clam Corbicula fluminea. Mutat Res 342:113-123 (1995).

182. Holland-Toomey B, Epel D. Multixenobiotic resistance in Urechis embryos: protection from environmental toxins. Biol Bull 185:355-386 (1993).

183. Kurelec B, Kr´ca S, Piv´cevi´c B, Ugarkovi´c D, Bachmann M, Imsiecke G, Müller WEG. Expression of P-glycoprotein gene in marine sponges. Identification and characterization of the 125-kDa drug-binding glycoprotein. Carcinogenesis 13:69-76 (1992).

184. Hollo Z, Homolya L, Davis CW, Sarkadi B. Calcein accumulation as a fluorometric functional assay of the multidrug transporter. Biochim Biophys Acta 1191:384-388 (1994).

185. Sarkadi B, Mueller M, Homolya L, Hollo Z, Seprodi J, Germann U, Gottesman MM, Price EM, Boucher RC. Interaction of bioactive hydrophobic peptides with the human multidrug transporter. FASEB J 8:766-770 (1994).

186. Landa V, Soldan T. The possibilities of mayfly faunistics to indicate environmental changes of large areas. In: Overview and Strategies of Ephemeroptera and Plecoptera (Alba-Tercedor J, Sanches-Ortega A, eds). Gainesville, FL:Sandhill Cram Press, 1991;559-566.

187. Burger J, ed. Before and After an Oil Spill: The Arthur Kill. New Brunswick, NJ:Rutgers University Press, 1994.

188. Cairns J, Gruber D. A comparison of methods and instrumentation of biological early warning systems. Water Resources Bull 16:261-266 (1980).

189. Kramer KJM, Botterweg J. Aquatic biological early warning systems: an overview. In: Bioindicators and Environmental Management (Jeffrey DW, Madden B, eds). New York:Academic Press, 1991;95-126.

190. Hughes GM. Changes in blood of fish following exposure to heavy metals and acid. In: Biological Monitoring of Environmental Pollution (Yasuno M, Whitton BA, eds). Hokkaido:Tokai University Press, 1988;11-17.

191. DW Nebert, Nelson DR, Feyereisen R. Evolution of the cytochrome P450 genes. Xenobiotica 19:1149-1160 (1989).

192. Brattsten LB. Ecological significance of mixed-function oxidations. Drug Metab Rev 10:35-58 (1979).

193. Gregus Z, Watkins JB, Thompson TN, Harvey MJ, Rozman K, Klaassen CD. Hepatic phase I and phase II biotransformations in quail and trout: comparison to other species commonly used in toxicity testing. Toxicol Appl Pharmacol 67:430-441 (1983).

194. NRC. Ecological Knowledge and Environmental Problem Solving. Washington:National Academy Press, 1986.

195. Burger J. Effects of oil on vegetation. In: Before and After an Oil Spill: The Arthur Kill (Burger J, ed). New Brunswick, NJ:Rutgers University Press, 1994;130-141.

196. Paine RT. Food web complexity and species diversity. Am Natur 100:65-75 (1966).

197. Anderson SL. Linking genotoxic responses and reproductive success in ecotoxicology. Environ Health Perspect 102:9-12 (1994).

198. Pimm SL.The complexity and stability of ecosystems. Nature 307:321-326 (1984).

199. Suter GW II. Ecological endpoints. In: Ecological Assessment of Hazardous Waste Sites (Warren-Hicks W, Parkhurst BR, Baker SS Jr, eds). Rpt 600/3-89/013. Washington:U.S. Environmental Protection Agency, 1989;13-20.

200. Suter GW II. Endpoints for regional ecological risk assessment. Environ Manage 14:9-20 (1990).

201. Burger J, Peakall D. Methods to assess the effects of chemicals on aquatic and terrestrial wildlife, particularly birds and mammals. In: Methods to Assess the Effects of Chemicals on Ecosystems (Linthurst RA, Bourdeau P, Tardiff RG, eds). Chichester:Wiley & Sons, 1995;291-306.

202. Schindler DW, Mills KH, Malley DF, Findlay DL, Shearer JA, Davies IJ, Turner MA, Linsey GA, Cruikshank DR. Long-term ecosystem stress: the effects of years of experimental acidification on a small lake. Science 228:1395-1401(1985).

203. Eastin C, Hoffman DJ, O'Leary CT. Lead accumulation and depression of delta-aminolevulinic acid dehydratase (ALAD) in young birds fed automotive waste oil. Arch Environ Contam Toxicol: 12031-35 (1983).

204. Needleman HL, Schell A, Bellinger D, Leviton A, Alfred EN. The long-term effects of exposure to lead in cildhood: an 11 year follow-up report. N Engl J Med 322083-88(1990).

205. ATSDR. Toxicological Profile for Lead. Atlanta, GA:Agency for Toxic Substances and Disease Registry, 1990.

206. Burger J. A risk assessment for lead in birds. J Toxicol Environ Health 45:369-396 (1995).

207. Grue CE, O'Shea JJ, Hoffman DJ. Lead concentrations and reproduction in highway-nesting barn swallows. Condor 860383-389 (1984).

208. Burger J. Behavioral effects of early postnatal lead exposure in herring gull (Larus argentatus) chicks. Pharmacol Biochem Behav 35:7-13 (1990).

209. Burger J, Gochfeld M. Behavioral impairment of lead-injected young herring gulls in nature. Fundam Appl Toxicol 23: 553-561 (1995).

210. Burger J, Gochfeld M. Lead and behavioral development in young herring gulls: effects of timing of exposure on individual recognition. Fundam Appl Toxicol 21:187-195 (1993).

211. Bellrose, FC. Lead poisoning as a mortality factor in waterfowl populations. Trans North Am Wildlife Conf 27:235-288 (1959).

212. Poland A, Glover E, Kende AS, DeCamp M, Giandomenico CM. 3,4,3´,4´-Tetrachloro azoxybenzene and azobenzene: potent inducers of aryl hydrocarbon hydroxylase. Science 194:627-630 (1976).

213. Poland A, Knutson JC. 2,3,7,8-Tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: examination of the mechanism of toxicity. Annu Rev Pharmacol Toxicol 22:517-554 (1982).

214. Brunstrom B, Reutergardh L. Differences in sensitivity of some avian species to the embryotoxicity of a PCB, 3,3´,4,4´-tetrachlorobiphenyl injected into the eggs. Environ Pollut 42A:37-45 (1986).

215. Brunstrom B, Lund J. Differences between chick and turkey embryos in sensitivity to 3,3´,4,4´-tetrachlorobiphenyl and in concentration/affinity of the hepatic receptor for 2,3,7,8-tetrachlorodibenzo-p-dioxin. Comp Biochem Physiol C Comp Pharmacol Toxicol 91:507-512 (1988).

216. Brunstrom B. Sensitivity of embryos from duck, goose, herring gull, and various chicken breeds to 3,3´,4,4´-tetrachlorobiphenyl. Poult Sci 67:52-57(1988).

217. Ashford NA. Policy considerations for human monitoring in the workplace. J Occup Med 28(2):563-568 (1986).

218. Ashford NA. Medical screening in the workplace: legal and ethical considerations. Semin Occup Med 1(1):67-79 (1986).

219. Atherley G, Johnston N, Tannassee M. Biological surveillance: rights conflict with rights. J Occup Med 28:958-965 (1986).

220. Lappé M, Gustafson J, Robin R. Ethical and social aspects of screening for genetic disease. N Engl J Med 206:1129-1132 (1972).

221. Lappé M. Ethical issues in testing for differential sensitivity to occupational hazards. J Occup Med 25:797-808 (1983).

222. Lappé M. Ethical concerns in occupational screening programs. J Occup Med 28:572-577 (1986).

223. Omenn GS. Predictive identification of hypersusceptible individuals. J Occup Med 24:369-374 (1982).

224. Perera FP. Molecular cancer epidemiology: a new tool in cancer prevention. J Natl Cancer Inst 78:887-898 (1987).

225. Perera FP, Santella R. Carcinogenesis. In: Molecular Epidemiology: Principles and Practices (Schulte P, Perera FP, eds). New York:Academic Press 1993; 277-300.

226. Schulte PA, Ringen K. Notification of workers at high risk: an emerging public health problem. Am J Public Health 74:485-490 (1984).

227. Schulte PA, Ringen K, Altekruse EB, Gullen WH, Davidson K, Anderson SS, Patton MG. Notification of a cohort of workers at risk of bladder cancer. J Occup Med 27:19-28 (1985).

228. Annas G. The bioethics of biomonitoring people for exposure to carcinogens. In: Molecular Dosimetry and Human Cancer: Analytical, Epidemiological, and Social Considerations (Groopman JD, Skipper PL, eds). Caldwell, NJ:Telford Press, 1991; 385-399.

229. Ashford NA, Spadafor CJ, Hattis DB, Caldart CC, eds. Monitoring the Worker for Exposure and Disease. Scientific, Legal, and Ethical Considerations in the use of Biomarkers. The Johns Hopkins Series in Environmental Toxicology. Baltimore:Johns Hopkins University Press, 1990.

230. Council of Europe. Draft Convention for the Protection of Human Rights and Dignity of the Human Being with Regard to the Application of Biology and Medicine: Bioethics Convention, and Explanatory Report. Strasbourg:Directorate of Legal Affairs, 1994.

231. Ettore E. The new genetic discourse in Finland: Exploring experts view within surveillance medicine. Helsinki:Helsinki Association of Finnish Muncipalities, 1996.

232. Grandjean P, Sorsa M. Ethical aspects of genetic predisposition to environmentally-related disease. Sci Total Environ 184:37-45 (1996).

233. Hulka BS, Wilcosky TC, Griffith JD, eds. Biological Markers in Epidemiology. New York:Oxford University Press, 1990.

234. Hulka BS. Overview of biological markers. In: Biological Markers in Epidemiology (Hulka BS Wilcosky TC Griffith JD, eds). New York:Oxford University Press, 1990;3-15.

235. Hulka BS. Methodologic issues in molecular epidemiology. In: Biological Markers in Epidemiology (Hulka BS, Wilcosky TC, Griffith JD, eds). New York:Oxford University Press, 1990; 214-226.

236. Hulka BS. Epidemiological studies using biological markers: issues for epidemiologists. Cancer Epidemiol Biomarkers Prev 1:13-19 (1991).

237. McMichael AJ. Invited Commentary--"Molecular epidemiology:" new pathway or new travelling companion? Am J Epidemiol 140:1-11 (1994).

238. Merletti F, Soskolne CL, Vineis P. Introduction to the epidemiological method as applied to occupational health and safety. In: ILO Encyclopedia of Occupational Health and Safety, 4th ed. Geneva:International Labour Office, in press.

239. Pearce N, de Sanjose S, Boffetta P, Kogevinas M, Saracci R, Savitz D. Limitations of biomarkers of exposure in cancer epidemiology. Epidemiology 6:190-194 (1995).

240. Privacy Commissioner of Canada. Genetic Testing and Privacy. Ottawa:Canadian National Research Council, 1992.

241. Rothman N, Stewart WF, Caporaso NE, Hayes RB. Misclassification of genetic susceptibility biomarkers: implications for case-control studies and cross-population comparisons. Cancer Epidemiol Biomarkers Prev 2:299-303 (1993).

242. Schulte PA. A conceptual and historical framework for molecular epidemiology. In: Molecular Epidemiology: Principles and Practices (Schulte P, Perera FP, eds). New York:Academic Press, 1993; 3-44.

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

244. Van Damme K, Casteleyn L, Heseltine E, Huici A, Sorsa M, van Larebeke N, Vineis P. Individual susceptibility and prevention of occupational diseases: scientific and ethical issues. J Occup Environ Med 37(1):91-99 (1995).

245. Vineis P. Uses of biochemical and biological markers in occupational epidemiology. Rev Epidemiol Santé Publique 40:S63-S69(1992).

246. Vineis P. Use of biomarkers in epidemiology. The example of metabolic susceptibility to cancer. Toxicol Lett 77:163-168 (1995).

247. Vineis P. Use of biochemical markers in environmental epidemiology. In: Environmental Epidemiology: Exposure and Disease (Bertollini R, Lebowitz MD, Saracci R, Savitz DA, eds). Boca Raton, FL:CRC Lewis Publishers, 1996;210-206.

248. Wilcosky TC, Griffith JD. Applications of biological markers. In: Biological Markers in Epidemiology (Hulka BS Wilcosky TC Griffith JD, eds). New York:Oxford University Press, 1990;16-27.

249. Greenberg MR, Martell J. Ethical dilemmas and solutions for risk assessment scientists. J Exp Anal Environ Epidemiol 2:381-389 (1992).

250. Soskolne CL. Epidemiology: questions of science, ethics, morality and law. Am J Epidemiol 129:1-18 (1989).

251. Summers C, Soskolne CL, Gotlieb C, Fawcett E, McClusky P. Do scientific and scholarly codes of ethics take social issues into account? Accountability Res 4:57-68 (1995).

252. Reece RD, Siegal HA. Studying people: a primer in the ethics of social research. Mercer, 1986.

253. Beauchamp TL, Childress JF. Principles of Biomedical Ethics. 4th ed. New York:Oxford University Press, 1994;336-337.

254. Shamoo AE, Annau Z. Data audit--historical perspective. In: Principles of Research Data Audit (Shamoo AE, ed). New York:Gordon & Breach, 1989;1-11.

255. CIOMS. International Guidelines for Ethical Review of Epidemiological Studies. Geneva:Council for International Organizations of Medical Sciences, 1991.

256. CIOMS. International Ethical Guidelines for Biomedical Research Involving Human Subjects. Geneva:Council for International Organizations of Medical Sciences, 1993.

257. Schimke RI. Gene amplification, drug resistance and cancer. Cancer Res 44:1235 (1984).

258. Beach LR, Palmiter RD. Amplification of the metallothionein gene 1 in cadmium-resistant mouse cells. Proc Natl Acad Sci USA 78:2110-2114 (1981).

259. Marx J. Oncogenes evoke new cancer therapies. Science 249:1376-1378 (1990).

260. Peltomäki P. DNA mismatch repair gene mutations in human cancer. Environ Health Perspect 105(Suppl 4):755-780 (1997).

261. Lewontin RC, Hartl DL. Population genetics in forensic DNA typing. Science 254:1745-1750 (1991).

262. Stokinger HE. Letter: Carcinogen standard. A letter to the Assistant Secretary, Occupational Safety and Health--and a response. J Occup Med 16(2):119-120 (1974).

263. Vainio H, Husgafvel-Pursiainen K. Elimination of environmental factors or elimination of individuals: biomarkers and prevention. J Occup Environ Med 37(1):12-13 (1995).

264. Gochfield M. Factors influencing susceptibility to metals. Environ Health Perspect 105(Suppl 4):817-822 (1997).

                       


[Table of Contents]

Last Update: June11, 1997