538
disagreement were highly dependent on the conditions of the patients observed. Comparisons between measurements of disagreement obtained from different patients may not be valid if it is likely that their conditions differ substantially. In the present study, the tasks presented to the four groups were not of equal difficulty, with group 4 having a smaller percentage of end-of-range observations to make (65%) than the other three groups (76 to 80%). As a minimum, such studies should include information on the distribution of GCS scores so that the validity of the comparisons can be
judged. For the future, further validation of the GCS is necessary. Even though further observer agreement studies are needed, they should be supplemented by studies that compare ratings with those by expert observers. For both types of studies, it seems essential that results be reported separately for those patients who are at intermediate levels of consciousness, and for those who are judged to be fully conscious or fully unconscious. Only by demonstrating high levels of accuracy for both patient conditions can the claims made about the reliability and validity of the GCS for the past fifteen years be fully supported. We thank Ms Glenn Gardner and Ms Elizabeth Pittman (La Trobe University), and Ms Judy King and Ms Claire Warmuth (Alfred Hospital) for their help; Miss E. June Allen and Prof Judith Parker for promoting the Alfred Hospital-La Trobe University Collaborative Nursing Research Project; the patients and nurses for their contribution; and Prof Dennis Lowther, Dr Ian Mackay, Dr Merrill Rowley, and Dr Peter Tutton of the Monash University Medical Faculty for their advice.
REFERENCES 1. Teasdale G, Jennett B. Assessment of coma and impaired consciousness. Lancet 1974; ii: 81-84. 2. Teasdale G, Knill-Jones R, Van der Sande J. Observer variability in assessing impaired consciousness and coma. J Neurol Neurosurg Psychiatry 1978; 41: 603-10. 3. Teasdale G. Assessing ’conscious level’. Nursing Times 1975; 72: 914-17. 4. Jennett B, Teasdale G. Aspects of coma after severe coma head injury. Lancet 1977; i: 878-81. 5. Jones C. Monitoring recovery after head injury: translating research into practice. J Neurosurg Nursing 1979; 11: 192-98. 6. Teasdale G, Gentleman D. The description of ’conscious level’: a case for the Glasgow coma scale. Scottish Med J 1982; 27: 7-9. 7. Allan D. Glasgow coma scale. Nursing Mirror 1984; 158: 31-34. 8. Stanczak DE, White JG, Gouview WD, et al. Assessment of consciousness following severe neurological insult. J Neurosurg 1984; 60: 955-60. 9. Starmark J, Stalhammar D, Holmgren E, Rosander B. A comparison of the Glasgow Coma Scale and the Reaction Level Scale (RLS85). J Neurosurg 1988; 69: 699-708. 10. Fielding K, Rowley G. Reliablity of assessments by skilled observers using the Glasgow Coma Scale. Aust J Adv Nursing 1990; 7: 13-17. 11. Cronbach LJ, Gleser GC, Nanda HK, Rajaratnam N. The dependability of behavioral measurements: theory of generalizabilty for scores and profiles. New York: Wiley, 1972. 12. Shavelson RJ, Webb NM, Rowley GL. Generalizability theory: new developments and novel applications. Am Psychol 1989; 44: 922-32. 13. Lord FM, Novick ML. Statistical theories of mental test scores, Reading. Massachusetts: Addison-Wesley, 1968. 14. Ingersoll GL, Leyden DB. The Glasgow coma scale for patients with head injuries. Crit Care Nurse 1987; 7: 26-32. 15. Starmark J, Holmgren E, Stalhammer D. Current reporting of responsiveness in acute cerebral disorders: a survey of the neurosurgical literature. J Neurosurg 1988; 69: 692-98 (see p. 696).
VIEWPOINT Prevention versus chemophobia: a defence of rodent carcinogenicity tests
Anxiety about chemicals found to be carcinogenic in rodent studies has been labelled "chemophobia".l The spread of this phobia has been attributed to "phantom hazards" identified by current cancer testing methods.2 If this argument is correct, public anxiety can be reduced; if not, arguments that the tests are meaningless may damage the long-term struggle to protect the health of the public. Cancer is no phantom; in the USA it affects more than one in four. In industrialised countries there have been increases in almost all forms of cancer over the past two decades in people over age 54 years (the ages at which most cancers occur).3 Thus, it seems reasonable to suspect that environmental factors contribute to the rise in cancer incidence (and mortality). The methodology that has been criticised1,2,4 is the use of the "estimated" maximum tolerated dose (EMTD) as the high-dose level in cancer bioassays. Some writers have described the EMTD as a massive dose. It is not. The maximum tolerated dose is defined as "the highest dose of the test agent during the chronic study that can be predicted not to alter the animals’ longevity from effects other than carcinogenicity ..."5. Moreover, the National Cancer Institute investigators who devised the cancer testing
protocols by administering known human carcinogens to laboratory animals found that cancer developed only in the animals exposed to the EMTD.6 Some critics2,4 conclude that the cancers that appear after the administration of a chemical at the EMTD are simply a reflection of increased cellular proliferation, not a result of a true carcinogenic response. According to these critics, a non-genotoxic substance given at the EMTD leads to such a high level of new cell proliferation that cell multiplication per se causes cancer. At lower doses, when there is no excess proliferation, there would be no cancer. This view, put simply, is that any substance given in a high enough dose becomes a carcinogen. For genotoxic carcinogens, the critics argue that the number of mutations leading to cancer response would vary at the same dose level depending on the amount of increased cellular proliferation induced by the test chemical at that dose level. The dose response below the level of increased cellular proliferation presumably would be ADDRESS Health Standards Program, Occupational Safety and Health Administration, Department of Labor, Room N3718, 200 Constitution Avenue, NW, Washington DC 20210, USA. (Dr P J
Infante, Dr PH)
539
non-linear and hence use of a dose-response model that is linear at low doses would result in an overestimate of the dose response at low exposure levels. The critics2.4 further argue that animals are poor surrogates for identifying human carcinogens. I deal below with these arguments.
Cellproliferation or organ toxicity and cancer The critics2,4 do not provide conclusive data that mitogenesis itself is a necessary and sufficient condition for the production of cancer. Several observations indicate that cell proliferation and organ toxicity themselves are not major determinants in the induction of cancer; instead they suggest that the carcinogenic process is more complex than what the critics seem to think. Almost 90% of the substances identified as carcinogens in the National Toxicology Program (NTP) bioassay program induced tumours in organs where there was no evidence of increased cellular toxicity.7 In animals given doses lower than the EMTD, over 90% of NTP carcinogens have led to a higher tumour incidence than that in the control animals but not all differences were statistically significant. If high-dose (EMTD) testing had not been done there would have been false-negative findings because for the 38% substances associated with a non-significant increase in tumour formation at the low dose, there was a significant rise at the EMTD. Such a high false-negative rate would have grave consequences from a public health perspective. The converse, proliferation without carcinogenesis, also seems to be true. In rats exposed to ethyl acrylate, a substance considered non-genotoxic, there was increased cellular proliferation after a 13-week exposure but no increase in cancer rate after approximately 19 months of follow-up.8 In two groups of mice treated first with then with dimethylbenz[a]anthracene (DMBA), tetradecanoyl phorbol acetate (TPA), the incidence of carcinoma was the same even though the rate of papillomas was three times greater in the high TPA dose group.9 Here, an increase in cellular proliferation did not alter the carcinogenic response. Likewise, in rats there is tremendous cellular proliferation in the liver after partial hepatectomy, yet liver cancer does not develop.1o Furthermore, although the adult bone-marrow, gastrointestinal tract, and skin and fetal organs are tissues undergoing continuous cellular proliferation, leukaemia, cancer of the small intestine, and skin cancer (in the absence of sunlight exposure) are uncommon among malignancies, and children are not all born with tumours. Liver toxicity has been observed without carcinogenicity, and liver tumours have been induced without accompanying organ toxicity in both the mouse and rat.’7 Thus, generalised organ toxicity per se does not seem to be related to liver cancer in rodents.
Qualitative evidence of cancer risk Ames and Gold2 believe that a high percentage (about 50%) of chemicals tested that are judged to be carcinogenic in the test is evidence that the cancer was induced because of the high dose administered (and the resultant increase in cellular turnover). Hence their conclusion that animal tests are not good predictors of human cancer response. However, existing data indicate that cancer bioassays are very good (qualitative) predictors of human cancer response. A review from the International Agency for Research on Cancer (IARC) reported that of 33 "human carcinogens" for which adequate experimental data were
available, 91 % were positive in one or more animal species." Furthermore, many agents first shown to cause cancer in laboratory animals were later, on the basis of epidemiological studies, proven to cause or highly suspected of causing cancer in man. Therefore, the sensitivity of animal cancer studies for predicting carcinogenicity in man, and the ability to recognise carcinogens through the rodent bioassay before identification of carcinogenicity in man, support the use of the current cancer bioassay protocol. The high percentage of chemicals tested that has been found to be carcinogenic is probably a reflection of an intelligent selection process-most chemicals have been subjected to testing because they were highly suspected of being carcinogens. The structural analogues of vinyl chloride were tested after the compound was shown to cause in animals and then in man. The chloromethanes and chloroethanes were tested because related chemicals had demonstrated carcinogenicity; and most of these related substances have proved to be carcinogens. In some cases, the metabolites of carcinogens have been tested. For example, phenol, hydroquinone, and catechol were tested because they are metabolites of benzene-a known human carcinogen. Phenol did not induce cancer, whereas hydroquinone and catechol did. cancer
Quantitative evidence of cancer risk The critics2,4argue that linear extrapolation leads to overestimateion of the cancer risk at low exposure levels. However, Bailar et al12 have shown that a linear model, when applied in the usual way by USA regulatory agencies, often underestimates lifetime cancer risk in the observable dose administration range. Bailar et al further presented six plausible reasons why cancer risks at lower doses may exceed those estimated by applying a linear formula to data obtained with higher doses.12 As a practical example, in bioassays for benzene 500 mg/kg body weight is taken as the high dose level in the rat.13 This dose is equivalent to about 600 ppm atmospheric benzene exposure for an 8-hour work day. Epidemiological study has shown that workers exposed to an average of 5 ppm atmospheric benzene for 7 years have their risk of acquiring myelogenous leukaemia increased four fold.14 Some of the individual cases were exposed to only 1 ppm benzene,14,15 an observation that is contrary to the comment by Ames and Gold2 that workers need high-level exposure for cancer to develop. In addition to the reasons cited by Bailar et a112 cancer potency may be underestimated by the current testing methods because animals are exposed to one test chemical at a time, whereas human beings are exposed, from prenatal life through childhood to adult life, to a large variety of carcinogens and other substances or conditions that may amplify carcinogenic response. Although little research has been conducted to evaluate interaction of exposure to carcinogens with other factors (ie, medication, immune deficiency, hormonal imbalances, and so on), additive or synergistic interaction between carcinogens and other toxic substances has been shown repeatedly. 16-18 The appropriateness of quantitatively extrapolating cancer test results in animals to man can be determined only by comparing toxicological with epidemiological findings. Analyses by Allen et al19 show a good correlation between such comparisons in animals with those in man. For substances regulated under section 6 (b) of the OSHA Act since 1980, data indicate that the risks estimated from animal
540
within an order of magnitude.2O-23 Thus, use of bioassay data in general for quantitative risk assessment seems acceptable and the current practice of using the EMTD as the high-dose level should not be changed. The addition of mechanistic studies may provide further knowledge that will enhance our ability to quantify cancer risk to man. and human studies
are
Alternatives to animal cancer studies
Although Ames and Gold2do not state that animal studies should be discontinued, the implication of their argument is a move to reduce the sensitivity of animal studies in identifying carcinogens-by use of lower doses. The result would be increased reliance on epidemiological studies. However, the obvious problems with relying upon observations in man are that: (1) the data arrive too late, if at all, which results in unnecessary deaths from preventable causes of cancer; (2) should a cohort of individuals be identifiable for study, exposure data for determining dose response usually are lacking; (3) the latency period for the carcinogenic response may be long, necessitating years of follow-up that may result in a tremendous cancer burden to groups of highly exposed individuals, and in great medical, administrative, and social costs to the public. It is a societal decision whether to rely upon animal cancer tests or wait for evidence of cancer in man before preventive action is taken. Some may favour the latter; those with a public health perspective favour the former. I thank my many colleagues, especially Ric Pfeffer, Marvm Schneiderman, James Huff, and Devra Davis for their helpful suggestions.
REFERENCES 1. Abelson PH. Testing for carcinogens with rodents. Science 1990; 249: 1357. 2. Ames BN, Gold LS. Too many rodent carcinogens. Mitogenesis increases mutagenesis. Science 1990; 249: 970-71. 3. Davis DL, Hoel D, Fox J, Lopez A. International trends in cancer mortality in France, West Germany, Italy, Japan, England and Wales, and the USA. Lancet 1990; ii: 474-81. 4. Cohen SM, Ellwein LB. Cell proliferation in carcinogenesis. Science 1990; 249: 1007-11. 5. Sontag JM, Page NP, Saffiotti U. Guidelines for carcinogen bioassay in small rodents. DHHS pub no NIH 76-801. Bethesda: National Cancer Institute, 1976. 6. McConnell E. The maximum tolerated dose: the debate. J Am Coll Tox
1989; 8: 1115-20. 7. Hoel DG, Haseman JK, Hogan MD, Huff J, McConnell EE. The impact of toxicity on carcinogenicity studies: implications for nsk assessment.
Carcinogenesis 1988; 9: 2045-52. Ghanayem BI, Maronpot RR, Matthews HB. Role of chemically induced cell proliferation in ethyl acrylate induced forestomach carcinogenesis. Prog Clin Biol Res (in press). 9. Hennings H, Shores R, Mitchell P, et al. Induction of papillomas with a high probability of conversion to malignancy. Carcinogenesis 1985; 6: 8.
1607. 10. Solt DB, Cayama E, Tsuda H, Enomoto K, Lee G, Farber E. Promotion of liver cancer development by brief exposure to dietary 2acetylaminofluorine plus partial hepatectomy or carbon tetrachloride. Cancer Res 1983; 43: 188-91. 11. Tomatis L, Antero A, Wilboum J, Shuker L. Human carcinogens so far identified. Jpn J Cancer Res 1989; 80: 795-807. 12. Bailar III JC, Crouch EAC, Shaikh R, Spiegelman D. One-hit models of carcinogenesis: conservative or not? Risk Analysis 1988; 8: 485-97. 13. Maltoni C, Conti B, Cotti G. Benzene: a multipotential carcinogen. Results of long-term bioassays preformed at the Bologna Institute of Oncology. Am J Industr Med 1983; 4: 589-630. 14. Bond GG, McLaren EA, Baldwin CL, Cook RR. An update of mortality among chemical workers exposed to benzene. Br J Industr Med 1986; 43: 685-91. 15. Ott MG, Townsend JC, Fishbeck WA, Langer RA. Mortality among individuals occupationally exposed to benzene. Arch Env Health 1978; 33: 3-10. 16. Bingham E, Neimeier RW, Reid JB. Multiple factors in carcinogenesis. Ann NY Acad Sci 1976; 271: 14-21.
17. Tomatis L. The value of long-term testing for the implementation of primary prevention. In: Hiatt HH, Watson JD, Winsten JA, eds. Origins of human cancer. Cold Spring Harbor: Cold Spring Harbor Conferences on Cell Proliferation, 1977; 4: 1339-57. 18. Saffiotti U. Identifying and defining chemical carcinogens. In: Hiatt HH, Watson JD, Winston JA, eds. Origins of human cancer. Cold Spnng Harbor: Cold Spring Harbor Conferences on Cell Proliferation, 1977; 4: 1311-26. 19. Allen AC, Crump KS, Shipp AM. Correlation between carcinogenic potency of chemicals in animals and humans. Risk Analysis 1988; 8: 531-47. 20. Occupational Safety and Health Administration. Occupational exposure to benzene: final rule. Fed Reg 1987; 52: 34460-578. 21. Occupational Safety and Health Administration. Occupational exposure to ethylene oxide: final rule. Fed Reg 1984; 49: 25734-809. 22. Occupational Safety and Health Administration. Occupational exposure to formaldehyde: final rule. Fed Reg 1987; 52: 46168-312. 23. Occupational Safety and Health Administration. Occupational exposure to cadmium: proposed rule. Fed Reg 1990; 55: 4052-4147.
BOOKSHELF The Shoulder Edited by C. A. Rockwood Jr and F. A. Matsen III.
Philadelphia/London: Saunders. 1990. Pp 1148 (2 vols). $175/125. ISBN 0-721628281. After many years without a major new textbook on the shoulder joint, two have been published in quick succession. The first is edited by Rockwood and Matsen, both of whom have contributed greatly to our knowledge of this most complex of joints; all but two of the 46 contributors hail from North America, with none from Europe-a surprising omission in that the stimulus for renewed interest in the shoulder began in the UK in 1969 with the introduction of total shoulder replacement into clinical practice. The embryology, anatomy, and biomechanics of the glenohumeral, acromioclavicular, and sternoclavicular joints, the disorders that affect these joints, and appropriate treatments are covered in great detail in two large volumes. Each chapter follows a more or less constant pattern: an historical review (where most non-US references are to be found) is followed by discussion of clinical presentation and methods of management, and chapters end with a very detailed description of the author’s preferred treatment. This format encourages a consistency of style which, together with the wealth of black-and-white photographs and diagrams, makes this a surprisingly readable textbook. There is occasional repetition which is exacerbated by the lack of cross-references to other chapters; on the other hand, each chapter is entirely self-contained. European clinicians will particularly welcome the observation that "in the vast majority of cases a working diagnosis can be reached following an appropriate history and careful clinical examination". Some minor errors and misprints are inevitable in a work of this size, but I was sad to see William Harvey rechristened John. Nevertheless, anyone with a passing interest in the shoulder, or any shoulder expert, will find virtually everything they would wish to know about the joint within these pages, or at least a reference to where further information might be found. It is undoubtedly a book for every orthopaedic library, and most of the ever-increasing number of surgeons with a special interest in the shoulder joint will want their own copy. Department of Orthopaedics, St Bartholomew’s Hospital, London EC1A 7BE, UK
ALAN W. F. LETTIN
disagreement were highly dependent on the conditions of the patients observed. Comparisons between measurements of disagreement obtained from different patients may not be valid if it is likely that their conditions differ substantially. In the present study, the tasks presented to the four groups were not of equal difficulty, with group 4 having a smaller percentage of end-of-range observations to make (65%) than the other three groups (76 to 80%). As a minimum, such studies should include information on the distribution of GCS scores so that the validity of the comparisons can be
judged. For the future, further validation of the GCS is necessary. Even though further observer agreement studies are needed, they should be supplemented by studies that compare ratings with those by expert observers. For both types of studies, it seems essential that results be reported separately for those patients who are at intermediate levels of consciousness, and for those who are judged to be fully conscious or fully unconscious. Only by demonstrating high levels of accuracy for both patient conditions can the claims made about the reliability and validity of the GCS for the past fifteen years be fully supported. We thank Ms Glenn Gardner and Ms Elizabeth Pittman (La Trobe University), and Ms Judy King and Ms Claire Warmuth (Alfred Hospital) for their help; Miss E. June Allen and Prof Judith Parker for promoting the Alfred Hospital-La Trobe University Collaborative Nursing Research Project; the patients and nurses for their contribution; and Prof Dennis Lowther, Dr Ian Mackay, Dr Merrill Rowley, and Dr Peter Tutton of the Monash University Medical Faculty for their advice.
REFERENCES 1. Teasdale G, Jennett B. Assessment of coma and impaired consciousness. Lancet 1974; ii: 81-84. 2. Teasdale G, Knill-Jones R, Van der Sande J. Observer variability in assessing impaired consciousness and coma. J Neurol Neurosurg Psychiatry 1978; 41: 603-10. 3. Teasdale G. Assessing ’conscious level’. Nursing Times 1975; 72: 914-17. 4. Jennett B, Teasdale G. Aspects of coma after severe coma head injury. Lancet 1977; i: 878-81. 5. Jones C. Monitoring recovery after head injury: translating research into practice. J Neurosurg Nursing 1979; 11: 192-98. 6. Teasdale G, Gentleman D. The description of ’conscious level’: a case for the Glasgow coma scale. Scottish Med J 1982; 27: 7-9. 7. Allan D. Glasgow coma scale. Nursing Mirror 1984; 158: 31-34. 8. Stanczak DE, White JG, Gouview WD, et al. Assessment of consciousness following severe neurological insult. J Neurosurg 1984; 60: 955-60. 9. Starmark J, Stalhammar D, Holmgren E, Rosander B. A comparison of the Glasgow Coma Scale and the Reaction Level Scale (RLS85). J Neurosurg 1988; 69: 699-708. 10. Fielding K, Rowley G. Reliablity of assessments by skilled observers using the Glasgow Coma Scale. Aust J Adv Nursing 1990; 7: 13-17. 11. Cronbach LJ, Gleser GC, Nanda HK, Rajaratnam N. The dependability of behavioral measurements: theory of generalizabilty for scores and profiles. New York: Wiley, 1972. 12. Shavelson RJ, Webb NM, Rowley GL. Generalizability theory: new developments and novel applications. Am Psychol 1989; 44: 922-32. 13. Lord FM, Novick ML. Statistical theories of mental test scores, Reading. Massachusetts: Addison-Wesley, 1968. 14. Ingersoll GL, Leyden DB. The Glasgow coma scale for patients with head injuries. Crit Care Nurse 1987; 7: 26-32. 15. Starmark J, Holmgren E, Stalhammer D. Current reporting of responsiveness in acute cerebral disorders: a survey of the neurosurgical literature. J Neurosurg 1988; 69: 692-98 (see p. 696).
VIEWPOINT Prevention versus chemophobia: a defence of rodent carcinogenicity tests
Anxiety about chemicals found to be carcinogenic in rodent studies has been labelled "chemophobia".l The spread of this phobia has been attributed to "phantom hazards" identified by current cancer testing methods.2 If this argument is correct, public anxiety can be reduced; if not, arguments that the tests are meaningless may damage the long-term struggle to protect the health of the public. Cancer is no phantom; in the USA it affects more than one in four. In industrialised countries there have been increases in almost all forms of cancer over the past two decades in people over age 54 years (the ages at which most cancers occur).3 Thus, it seems reasonable to suspect that environmental factors contribute to the rise in cancer incidence (and mortality). The methodology that has been criticised1,2,4 is the use of the "estimated" maximum tolerated dose (EMTD) as the high-dose level in cancer bioassays. Some writers have described the EMTD as a massive dose. It is not. The maximum tolerated dose is defined as "the highest dose of the test agent during the chronic study that can be predicted not to alter the animals’ longevity from effects other than carcinogenicity ..."5. Moreover, the National Cancer Institute investigators who devised the cancer testing
protocols by administering known human carcinogens to laboratory animals found that cancer developed only in the animals exposed to the EMTD.6 Some critics2,4 conclude that the cancers that appear after the administration of a chemical at the EMTD are simply a reflection of increased cellular proliferation, not a result of a true carcinogenic response. According to these critics, a non-genotoxic substance given at the EMTD leads to such a high level of new cell proliferation that cell multiplication per se causes cancer. At lower doses, when there is no excess proliferation, there would be no cancer. This view, put simply, is that any substance given in a high enough dose becomes a carcinogen. For genotoxic carcinogens, the critics argue that the number of mutations leading to cancer response would vary at the same dose level depending on the amount of increased cellular proliferation induced by the test chemical at that dose level. The dose response below the level of increased cellular proliferation presumably would be ADDRESS Health Standards Program, Occupational Safety and Health Administration, Department of Labor, Room N3718, 200 Constitution Avenue, NW, Washington DC 20210, USA. (Dr P J
Infante, Dr PH)
539
non-linear and hence use of a dose-response model that is linear at low doses would result in an overestimate of the dose response at low exposure levels. The critics2.4 further argue that animals are poor surrogates for identifying human carcinogens. I deal below with these arguments.
Cellproliferation or organ toxicity and cancer The critics2,4 do not provide conclusive data that mitogenesis itself is a necessary and sufficient condition for the production of cancer. Several observations indicate that cell proliferation and organ toxicity themselves are not major determinants in the induction of cancer; instead they suggest that the carcinogenic process is more complex than what the critics seem to think. Almost 90% of the substances identified as carcinogens in the National Toxicology Program (NTP) bioassay program induced tumours in organs where there was no evidence of increased cellular toxicity.7 In animals given doses lower than the EMTD, over 90% of NTP carcinogens have led to a higher tumour incidence than that in the control animals but not all differences were statistically significant. If high-dose (EMTD) testing had not been done there would have been false-negative findings because for the 38% substances associated with a non-significant increase in tumour formation at the low dose, there was a significant rise at the EMTD. Such a high false-negative rate would have grave consequences from a public health perspective. The converse, proliferation without carcinogenesis, also seems to be true. In rats exposed to ethyl acrylate, a substance considered non-genotoxic, there was increased cellular proliferation after a 13-week exposure but no increase in cancer rate after approximately 19 months of follow-up.8 In two groups of mice treated first with then with dimethylbenz[a]anthracene (DMBA), tetradecanoyl phorbol acetate (TPA), the incidence of carcinoma was the same even though the rate of papillomas was three times greater in the high TPA dose group.9 Here, an increase in cellular proliferation did not alter the carcinogenic response. Likewise, in rats there is tremendous cellular proliferation in the liver after partial hepatectomy, yet liver cancer does not develop.1o Furthermore, although the adult bone-marrow, gastrointestinal tract, and skin and fetal organs are tissues undergoing continuous cellular proliferation, leukaemia, cancer of the small intestine, and skin cancer (in the absence of sunlight exposure) are uncommon among malignancies, and children are not all born with tumours. Liver toxicity has been observed without carcinogenicity, and liver tumours have been induced without accompanying organ toxicity in both the mouse and rat.’7 Thus, generalised organ toxicity per se does not seem to be related to liver cancer in rodents.
Qualitative evidence of cancer risk Ames and Gold2 believe that a high percentage (about 50%) of chemicals tested that are judged to be carcinogenic in the test is evidence that the cancer was induced because of the high dose administered (and the resultant increase in cellular turnover). Hence their conclusion that animal tests are not good predictors of human cancer response. However, existing data indicate that cancer bioassays are very good (qualitative) predictors of human cancer response. A review from the International Agency for Research on Cancer (IARC) reported that of 33 "human carcinogens" for which adequate experimental data were
available, 91 % were positive in one or more animal species." Furthermore, many agents first shown to cause cancer in laboratory animals were later, on the basis of epidemiological studies, proven to cause or highly suspected of causing cancer in man. Therefore, the sensitivity of animal cancer studies for predicting carcinogenicity in man, and the ability to recognise carcinogens through the rodent bioassay before identification of carcinogenicity in man, support the use of the current cancer bioassay protocol. The high percentage of chemicals tested that has been found to be carcinogenic is probably a reflection of an intelligent selection process-most chemicals have been subjected to testing because they were highly suspected of being carcinogens. The structural analogues of vinyl chloride were tested after the compound was shown to cause in animals and then in man. The chloromethanes and chloroethanes were tested because related chemicals had demonstrated carcinogenicity; and most of these related substances have proved to be carcinogens. In some cases, the metabolites of carcinogens have been tested. For example, phenol, hydroquinone, and catechol were tested because they are metabolites of benzene-a known human carcinogen. Phenol did not induce cancer, whereas hydroquinone and catechol did. cancer
Quantitative evidence of cancer risk The critics2,4argue that linear extrapolation leads to overestimateion of the cancer risk at low exposure levels. However, Bailar et al12 have shown that a linear model, when applied in the usual way by USA regulatory agencies, often underestimates lifetime cancer risk in the observable dose administration range. Bailar et al further presented six plausible reasons why cancer risks at lower doses may exceed those estimated by applying a linear formula to data obtained with higher doses.12 As a practical example, in bioassays for benzene 500 mg/kg body weight is taken as the high dose level in the rat.13 This dose is equivalent to about 600 ppm atmospheric benzene exposure for an 8-hour work day. Epidemiological study has shown that workers exposed to an average of 5 ppm atmospheric benzene for 7 years have their risk of acquiring myelogenous leukaemia increased four fold.14 Some of the individual cases were exposed to only 1 ppm benzene,14,15 an observation that is contrary to the comment by Ames and Gold2 that workers need high-level exposure for cancer to develop. In addition to the reasons cited by Bailar et a112 cancer potency may be underestimated by the current testing methods because animals are exposed to one test chemical at a time, whereas human beings are exposed, from prenatal life through childhood to adult life, to a large variety of carcinogens and other substances or conditions that may amplify carcinogenic response. Although little research has been conducted to evaluate interaction of exposure to carcinogens with other factors (ie, medication, immune deficiency, hormonal imbalances, and so on), additive or synergistic interaction between carcinogens and other toxic substances has been shown repeatedly. 16-18 The appropriateness of quantitatively extrapolating cancer test results in animals to man can be determined only by comparing toxicological with epidemiological findings. Analyses by Allen et al19 show a good correlation between such comparisons in animals with those in man. For substances regulated under section 6 (b) of the OSHA Act since 1980, data indicate that the risks estimated from animal
540
within an order of magnitude.2O-23 Thus, use of bioassay data in general for quantitative risk assessment seems acceptable and the current practice of using the EMTD as the high-dose level should not be changed. The addition of mechanistic studies may provide further knowledge that will enhance our ability to quantify cancer risk to man. and human studies
are
Alternatives to animal cancer studies
Although Ames and Gold2do not state that animal studies should be discontinued, the implication of their argument is a move to reduce the sensitivity of animal studies in identifying carcinogens-by use of lower doses. The result would be increased reliance on epidemiological studies. However, the obvious problems with relying upon observations in man are that: (1) the data arrive too late, if at all, which results in unnecessary deaths from preventable causes of cancer; (2) should a cohort of individuals be identifiable for study, exposure data for determining dose response usually are lacking; (3) the latency period for the carcinogenic response may be long, necessitating years of follow-up that may result in a tremendous cancer burden to groups of highly exposed individuals, and in great medical, administrative, and social costs to the public. It is a societal decision whether to rely upon animal cancer tests or wait for evidence of cancer in man before preventive action is taken. Some may favour the latter; those with a public health perspective favour the former. I thank my many colleagues, especially Ric Pfeffer, Marvm Schneiderman, James Huff, and Devra Davis for their helpful suggestions.
REFERENCES 1. Abelson PH. Testing for carcinogens with rodents. Science 1990; 249: 1357. 2. Ames BN, Gold LS. Too many rodent carcinogens. Mitogenesis increases mutagenesis. Science 1990; 249: 970-71. 3. Davis DL, Hoel D, Fox J, Lopez A. International trends in cancer mortality in France, West Germany, Italy, Japan, England and Wales, and the USA. Lancet 1990; ii: 474-81. 4. Cohen SM, Ellwein LB. Cell proliferation in carcinogenesis. Science 1990; 249: 1007-11. 5. Sontag JM, Page NP, Saffiotti U. Guidelines for carcinogen bioassay in small rodents. DHHS pub no NIH 76-801. Bethesda: National Cancer Institute, 1976. 6. McConnell E. The maximum tolerated dose: the debate. J Am Coll Tox
1989; 8: 1115-20. 7. Hoel DG, Haseman JK, Hogan MD, Huff J, McConnell EE. The impact of toxicity on carcinogenicity studies: implications for nsk assessment.
Carcinogenesis 1988; 9: 2045-52. Ghanayem BI, Maronpot RR, Matthews HB. Role of chemically induced cell proliferation in ethyl acrylate induced forestomach carcinogenesis. Prog Clin Biol Res (in press). 9. Hennings H, Shores R, Mitchell P, et al. Induction of papillomas with a high probability of conversion to malignancy. Carcinogenesis 1985; 6: 8.
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BOOKSHELF The Shoulder Edited by C. A. Rockwood Jr and F. A. Matsen III.
Philadelphia/London: Saunders. 1990. Pp 1148 (2 vols). $175/125. ISBN 0-721628281. After many years without a major new textbook on the shoulder joint, two have been published in quick succession. The first is edited by Rockwood and Matsen, both of whom have contributed greatly to our knowledge of this most complex of joints; all but two of the 46 contributors hail from North America, with none from Europe-a surprising omission in that the stimulus for renewed interest in the shoulder began in the UK in 1969 with the introduction of total shoulder replacement into clinical practice. The embryology, anatomy, and biomechanics of the glenohumeral, acromioclavicular, and sternoclavicular joints, the disorders that affect these joints, and appropriate treatments are covered in great detail in two large volumes. Each chapter follows a more or less constant pattern: an historical review (where most non-US references are to be found) is followed by discussion of clinical presentation and methods of management, and chapters end with a very detailed description of the author’s preferred treatment. This format encourages a consistency of style which, together with the wealth of black-and-white photographs and diagrams, makes this a surprisingly readable textbook. There is occasional repetition which is exacerbated by the lack of cross-references to other chapters; on the other hand, each chapter is entirely self-contained. European clinicians will particularly welcome the observation that "in the vast majority of cases a working diagnosis can be reached following an appropriate history and careful clinical examination". Some minor errors and misprints are inevitable in a work of this size, but I was sad to see William Harvey rechristened John. Nevertheless, anyone with a passing interest in the shoulder, or any shoulder expert, will find virtually everything they would wish to know about the joint within these pages, or at least a reference to where further information might be found. It is undoubtedly a book for every orthopaedic library, and most of the ever-increasing number of surgeons with a special interest in the shoulder joint will want their own copy. Department of Orthopaedics, St Bartholomew’s Hospital, London EC1A 7BE, UK
ALAN W. F. LETTIN
