- Email: [email protected]
CADMIUM TOXICITY
1241 PROPORTION OF SINGLE WOMEN WITH BREAST CANCER AND BY SINGLE YEAR OF CERVIX IN
NON-BREAST CANCER
SITU)
(MINUS
AGE
exists, and it has been discussed by others, including Logan.’
My hypothesis is based as much on the effect of the sex of the offspring as it is on the cross-over of breast-cancer rates among married and single women in their late 30s. In biological terms, our data on the sex of the offspring2 were more influential in the formulation of the hypothesis. Further study of the relationship between pregnancy and breast-cancer risk is needed, concentrating particularly on the sex of the first off-
spring. Bureau of Cancer Control, New York State Department of Health, E.S.P. Tower Building, Albany, New York 12237, U.S.A.
DWIGHT T.
JANERICH
CADMIUM TOXICITY
*Negative
values indicate
an excess
of married
women
among breast
cancer cases.
may be an artifact of rapidly changing marriage-rates among young women. I have re-examined our current registry data by one year intervals as Doll suggests. The table compares the proportion of single women in one year age intervals for breast cancer and all other cancers (minus cervix in situ). In one year age groups there is considerable variability in the proportions, as one might expect. Nevertheless, until 40 years of age there is
women
of single breast-cancer patients compared After 40, excess begins to appear. The crossing over of breast-cancer incidence-rates among single and married women in their 30s is shown in the figure, which was also prepared from registry data. In terms of age-specific rates as well as the proportions of single women, there is clear evidence of a cross-over of incidence associated with the marital status for women in their mid to late 30s. This is presumably pregnancy-related. Therefore, I still believe a cross-over
clearly to
a
deficiency
the other
cancers.
Incidence of breast
cancer
in married and
single
women
by
age.
SIR,-We read with interest the pilot survey by Dr Carruthers and Mr Smith (April 21, p. 845) reporting evidence of cadmium toxicity in Shipham residents. We appreciate the difficulties in establishing a cause-effect relation between a general environmental pollutant and alleged health effects and the temptation of attributing observed illnesses to increased pollutant body burdens. The difficulties are compounded when exposures become the subject of publicity and notoriety. Under such circumstances it becomes very difficult to avoid volunteer bias unless rigorous randomised sampling procedures are used. The method of volunteer identification in the Shipham study and the impressive list of associated medical conditions found among the study participants suggest that the sample was strongly biased toward the anxious and overtly ill. Only one person over the age of 55was unexposed. Thus any comparison of exposure will be confounded by age: since age is correlated with blood-pressure and renal function controlling for age, by case matching for example, is essential. In an attempt to assess the Shipham data statistically we constructed a cadmium-exposure index by multiplying residence-time in Shipham and the percent of ingested vegetables grown in high-cadmium soils. This assumes that the proportion of vegetables homegrown has been constant over an individual’s residence, but is perhaps the best exposure index available. This index was significantly correlated only with the two variables from which it was formed and not with any blood or urine measurement. Similarly, blood-cadmium was significantly correlated only with serum-urea, and this correlation is negative (i.e., in the wrong direction from expected results). Blood and urine values were also tested for an association with smoking: all except blood-cadmium, which is increased in smokers,3 have odds ratios of less than one (i.e., smoking seems protective). However, this obviously counter-intuitive finding did not reach statistical significance. 6 of 6 smokers had increased blood-cadmium as did 15 of 24 non-smokers. Thus, smoking should have been carefully controlled for in the study. The one occupationally exposed individual obviously should not be included in a series of persons having only general environmental exposure and was omitted in our calculations. We agree that the nephrotoxicity of excessive cadmium absorption is firmly established, resulting in a mixed tubular and glomerular proteinuria.4 Hypertension is not "consistently" found after cadmium administration to laboratory animals, but is rather difficult to induce5 and appears to be strain specific.6 The association between cadmium exposure and human hypertension is tenuous at best and appears to be a spurious association resulting from the presence of confounding variables, especially age and smoking.’ Data from Japan, 1. Logan, W. P. D. Lancet, 1953, i, 1199. 2. Janerich, D. T., Glebatis, D., Flink, E., Hoff, M. J. chron. Dis (in the press). 3. Enbrodt, H. J., and others. Naturwissenschaften, 1976, 63, 148. 4. Bernard, A., and others. Toxicology, 1978, 10, 369. 5. Lener, J., Bibr, B. Lancet, 1978, i, 970 6. Øhanian, E. N., Iwai, J. Contribution to International Conference on Cadmium, held at National Institutes of Health, on June 6-9, 1978. 7. Østergaard, K. Lancet, 1977, i, 677.
1242 the only country with widespread general environmental cadmium pollution, do not confirm this association.8 In addition, aminoaciduria, noted to be absent in Shipham volunteers, is a relatively consistent finding in both man and animals with cadmium-induced renal dysfunction.9;1O Shipham soils are heavily contaminated with zinc-mining spoils. Zinc has been shown to be a physiological antagonist to cadmium and is protective against a wide range of toxicological end-points, including experimentally induced hypertension"1 and tumorigenicl2 and teratogenic effects.13 Any evaluation of Shipham residents should include an assessment of dietary zinc and other nutrients as well as cadmium absorption. These points are raised not to disparage the effort in Shipham but to point out the need for a carefully designed and controlled epidemiological study. Anything less will only serve to further confound the very complex dose-response relationship of cadmium in man. D. F. KRAEMER
J. B. LUCAS H. R.PAHRENPAHREN
mium in other body organs may, indeed, differ from those which follow the inhalation of industrial dusts. Department of Pathology, University of Health Sciences, Chicago Medical School, Chicago, Illinois 60612, U.S.A.
STEPHEN R. GREENBERG
INCREASING INCIDENCE OF MALARIA IN BRITAIN
SIR,-During the past ten years, the number of cases of malaria imported into Britain has increased. Between 1976 and 1978, 401 cases have been seen at Hillingdon Hospital, West London, one of the hospitals serving Heathrow airport. All but eleven of these cases have come from the Asian subcontinent. These Asian cases fall into two main groups-new immigrants and U.K. resident Asians returning to India as tourists (see table). 388 of these patients had Plasmodium vivax, 1 had P. falciparum, and 1 had P. ovale. The data from these cases demonstrates the following: CASES OF MALARIA SEEN AT HILLINGDON HOSPITAL
1976-78
H. R.
U.S. Environmental Protection Cincinnati, Ohio 45268, U.S.A.
Agency,
J. A. RYAN N. E. KOWAL
Dr Roels and colleagues (Jan. 27, kidney is affected by cadmium pollution is because the lung is traditionally considered to be the
SIR,-The report by p.
222)
notable
that the
prime target for all the noxious substances to which man exposes himself. We have begun an investigation of the maximal anatomical "baseline" effects in animal tissues when chemically pure cadmium is introduced. Single wires of metallic cadmium (0.33 mm x 5 mm, each weighing about 14 mg) were inserted aseptically into the right renal cortices of 100 mature Sprague-Dawley rats. The technique is fully described elsewhere.’ Microscopic examination of kidneys from animals killed at weekly intervals for 16 weeks revealed a striking destruction and fibrous replacement of extensive areas of the renal cortex, beginning at about the fourth week. The parenchymal injury reached far beyond the site of wire implantation, and was more extensive than would seem warranted by the physical dimensions of the implant. The renal arterioles became thickened after about 8 to 10 weeks of cadmium exposure-an observation consistent with that of Kanisawa and Schroeder.2 Although blood-pressure was not measured the anatomical changes were compatible with evidence from studies of cadmium-induced hypertension in animals.3.4 The vascular lesions, like the parenchymal changes, were often found at a distance from the wire implant. Additional data, obtained by polarised light microscopy5 and fluorescent microscopy (unpublished), suggested that there might be a cadmium antigen-antibody-like complex in the area of injury-a possibility already suspected for other metals. 6.7 The potential for cadmium damage to the kidney seems, therefore, to be greater than the chemical urinalysis data suggests. I agree with Dr Harvey and colleagues (March 10, p. 551) that the results of the environmental exposure to cad8. 9. 10.
Nogawa, K., Kawana, S. J. Iuzen med. Soc. 1969, 66, 357. Kazantzis, G., and others. Q. Jl Med. 1963, 32, 165. Tsuchiya, K. in Cadmium Studies in Japan: a review (edited by K. Tsuchiya); p.276. Amsterdam, 1978. 11. Schroeder, H. A., Buckman, J. Archs envir. Hlth, 1967, 14, 693. 12. Gunn, S. A., and others. J. natn Cancer Inst. 1963, 31, 745. 13. Ferm, V. H., Carpenter, S.J. Nature, 1967, 216, 1123. 1. Greenberg, S. R. Urol. Internat. 1979, 34, 126. 2. Kanisawa, M., Schroeder, H. A. Exp. molec. Path. 1969, 10, 81. 3. Schroeder, H. A., Vinton, W. H. Am. J. Physiol. 1962, 202, 515. 4. Schroeder, H. A. ibid. 1964, 207, 62. 5. Greenberg, S. R. Toxicol. Path. 1978, 6, 26. 6. Raffel, S. Immunology, p.361, New York, 1961. 7. Epstein, W. L., Skahen, J. R., Krasnobrod, H. J. invest. Dermat. 1962, 38, 223.
(1) The proportion of cases in tourists is increasing more rapidly than in the immigrant group (see table). (2) Most cases present within 2 months of arrival in this country although the spectrum spans 13 months. (3) Surprisingly, immigrants present earlier than tourists, with a median difference of 2.1 months in the incubation period between the two groups. The role of immunity in this area is unclear. (4) None of the malaria patients had taken adequate prophylaxis.
Distribution of cases of malaria imported from India, trend and time-series extrapolation for 1979. x-x-x=cases
recorded; 0
...
0
...
showing
0=time-series forecast
analysis was carried out to predict future The total anticipated for 1979 is 255 (see figure). If other factors do not change (e.g., the prevalence of P. vivax in the Punjab and immigration laws), the expected increase represents a considerable load on the laboratory and on clinical services. The routine workload is frequently disrupted by urgent examination of suspected cases to exclude P. falciparum. Other hospitals’serving comparable Asian immigrant groups can anticipate similar increases. Clearly there is a need for medical education in the use of malaria prophylaxis in risk groups in the U.K. as well as abroad. A time-series
cases.
Department of Hæmatology, Hillingdon Hospital, Uxbridge, Middlesex; and Department of Statistics, Polytechnic of the South Bank,
RUTH WARWICK G. SWIMER
London SE1
R. P. BRITT
NON-BREAST CANCER
SITU)
(MINUS
AGE
exists, and it has been discussed by others, including Logan.’
My hypothesis is based as much on the effect of the sex of the offspring as it is on the cross-over of breast-cancer rates among married and single women in their late 30s. In biological terms, our data on the sex of the offspring2 were more influential in the formulation of the hypothesis. Further study of the relationship between pregnancy and breast-cancer risk is needed, concentrating particularly on the sex of the first off-
spring. Bureau of Cancer Control, New York State Department of Health, E.S.P. Tower Building, Albany, New York 12237, U.S.A.
DWIGHT T.
JANERICH
CADMIUM TOXICITY
*Negative
values indicate
an excess
of married
women
among breast
cancer cases.
may be an artifact of rapidly changing marriage-rates among young women. I have re-examined our current registry data by one year intervals as Doll suggests. The table compares the proportion of single women in one year age intervals for breast cancer and all other cancers (minus cervix in situ). In one year age groups there is considerable variability in the proportions, as one might expect. Nevertheless, until 40 years of age there is
women
of single breast-cancer patients compared After 40, excess begins to appear. The crossing over of breast-cancer incidence-rates among single and married women in their 30s is shown in the figure, which was also prepared from registry data. In terms of age-specific rates as well as the proportions of single women, there is clear evidence of a cross-over of incidence associated with the marital status for women in their mid to late 30s. This is presumably pregnancy-related. Therefore, I still believe a cross-over
clearly to
a
deficiency
the other
cancers.
Incidence of breast
cancer
in married and
single
women
by
age.
SIR,-We read with interest the pilot survey by Dr Carruthers and Mr Smith (April 21, p. 845) reporting evidence of cadmium toxicity in Shipham residents. We appreciate the difficulties in establishing a cause-effect relation between a general environmental pollutant and alleged health effects and the temptation of attributing observed illnesses to increased pollutant body burdens. The difficulties are compounded when exposures become the subject of publicity and notoriety. Under such circumstances it becomes very difficult to avoid volunteer bias unless rigorous randomised sampling procedures are used. The method of volunteer identification in the Shipham study and the impressive list of associated medical conditions found among the study participants suggest that the sample was strongly biased toward the anxious and overtly ill. Only one person over the age of 55was unexposed. Thus any comparison of exposure will be confounded by age: since age is correlated with blood-pressure and renal function controlling for age, by case matching for example, is essential. In an attempt to assess the Shipham data statistically we constructed a cadmium-exposure index by multiplying residence-time in Shipham and the percent of ingested vegetables grown in high-cadmium soils. This assumes that the proportion of vegetables homegrown has been constant over an individual’s residence, but is perhaps the best exposure index available. This index was significantly correlated only with the two variables from which it was formed and not with any blood or urine measurement. Similarly, blood-cadmium was significantly correlated only with serum-urea, and this correlation is negative (i.e., in the wrong direction from expected results). Blood and urine values were also tested for an association with smoking: all except blood-cadmium, which is increased in smokers,3 have odds ratios of less than one (i.e., smoking seems protective). However, this obviously counter-intuitive finding did not reach statistical significance. 6 of 6 smokers had increased blood-cadmium as did 15 of 24 non-smokers. Thus, smoking should have been carefully controlled for in the study. The one occupationally exposed individual obviously should not be included in a series of persons having only general environmental exposure and was omitted in our calculations. We agree that the nephrotoxicity of excessive cadmium absorption is firmly established, resulting in a mixed tubular and glomerular proteinuria.4 Hypertension is not "consistently" found after cadmium administration to laboratory animals, but is rather difficult to induce5 and appears to be strain specific.6 The association between cadmium exposure and human hypertension is tenuous at best and appears to be a spurious association resulting from the presence of confounding variables, especially age and smoking.’ Data from Japan, 1. Logan, W. P. D. Lancet, 1953, i, 1199. 2. Janerich, D. T., Glebatis, D., Flink, E., Hoff, M. J. chron. Dis (in the press). 3. Enbrodt, H. J., and others. Naturwissenschaften, 1976, 63, 148. 4. Bernard, A., and others. Toxicology, 1978, 10, 369. 5. Lener, J., Bibr, B. Lancet, 1978, i, 970 6. Øhanian, E. N., Iwai, J. Contribution to International Conference on Cadmium, held at National Institutes of Health, on June 6-9, 1978. 7. Østergaard, K. Lancet, 1977, i, 677.
1242 the only country with widespread general environmental cadmium pollution, do not confirm this association.8 In addition, aminoaciduria, noted to be absent in Shipham volunteers, is a relatively consistent finding in both man and animals with cadmium-induced renal dysfunction.9;1O Shipham soils are heavily contaminated with zinc-mining spoils. Zinc has been shown to be a physiological antagonist to cadmium and is protective against a wide range of toxicological end-points, including experimentally induced hypertension"1 and tumorigenicl2 and teratogenic effects.13 Any evaluation of Shipham residents should include an assessment of dietary zinc and other nutrients as well as cadmium absorption. These points are raised not to disparage the effort in Shipham but to point out the need for a carefully designed and controlled epidemiological study. Anything less will only serve to further confound the very complex dose-response relationship of cadmium in man. D. F. KRAEMER
J. B. LUCAS H. R.PAHRENPAHREN
mium in other body organs may, indeed, differ from those which follow the inhalation of industrial dusts. Department of Pathology, University of Health Sciences, Chicago Medical School, Chicago, Illinois 60612, U.S.A.
STEPHEN R. GREENBERG
INCREASING INCIDENCE OF MALARIA IN BRITAIN
SIR,-During the past ten years, the number of cases of malaria imported into Britain has increased. Between 1976 and 1978, 401 cases have been seen at Hillingdon Hospital, West London, one of the hospitals serving Heathrow airport. All but eleven of these cases have come from the Asian subcontinent. These Asian cases fall into two main groups-new immigrants and U.K. resident Asians returning to India as tourists (see table). 388 of these patients had Plasmodium vivax, 1 had P. falciparum, and 1 had P. ovale. The data from these cases demonstrates the following: CASES OF MALARIA SEEN AT HILLINGDON HOSPITAL
1976-78
H. R.
U.S. Environmental Protection Cincinnati, Ohio 45268, U.S.A.
Agency,
J. A. RYAN N. E. KOWAL
Dr Roels and colleagues (Jan. 27, kidney is affected by cadmium pollution is because the lung is traditionally considered to be the
SIR,-The report by p.
222)
notable
that the
prime target for all the noxious substances to which man exposes himself. We have begun an investigation of the maximal anatomical "baseline" effects in animal tissues when chemically pure cadmium is introduced. Single wires of metallic cadmium (0.33 mm x 5 mm, each weighing about 14 mg) were inserted aseptically into the right renal cortices of 100 mature Sprague-Dawley rats. The technique is fully described elsewhere.’ Microscopic examination of kidneys from animals killed at weekly intervals for 16 weeks revealed a striking destruction and fibrous replacement of extensive areas of the renal cortex, beginning at about the fourth week. The parenchymal injury reached far beyond the site of wire implantation, and was more extensive than would seem warranted by the physical dimensions of the implant. The renal arterioles became thickened after about 8 to 10 weeks of cadmium exposure-an observation consistent with that of Kanisawa and Schroeder.2 Although blood-pressure was not measured the anatomical changes were compatible with evidence from studies of cadmium-induced hypertension in animals.3.4 The vascular lesions, like the parenchymal changes, were often found at a distance from the wire implant. Additional data, obtained by polarised light microscopy5 and fluorescent microscopy (unpublished), suggested that there might be a cadmium antigen-antibody-like complex in the area of injury-a possibility already suspected for other metals. 6.7 The potential for cadmium damage to the kidney seems, therefore, to be greater than the chemical urinalysis data suggests. I agree with Dr Harvey and colleagues (March 10, p. 551) that the results of the environmental exposure to cad8. 9. 10.
Nogawa, K., Kawana, S. J. Iuzen med. Soc. 1969, 66, 357. Kazantzis, G., and others. Q. Jl Med. 1963, 32, 165. Tsuchiya, K. in Cadmium Studies in Japan: a review (edited by K. Tsuchiya); p.276. Amsterdam, 1978. 11. Schroeder, H. A., Buckman, J. Archs envir. Hlth, 1967, 14, 693. 12. Gunn, S. A., and others. J. natn Cancer Inst. 1963, 31, 745. 13. Ferm, V. H., Carpenter, S.J. Nature, 1967, 216, 1123. 1. Greenberg, S. R. Urol. Internat. 1979, 34, 126. 2. Kanisawa, M., Schroeder, H. A. Exp. molec. Path. 1969, 10, 81. 3. Schroeder, H. A., Vinton, W. H. Am. J. Physiol. 1962, 202, 515. 4. Schroeder, H. A. ibid. 1964, 207, 62. 5. Greenberg, S. R. Toxicol. Path. 1978, 6, 26. 6. Raffel, S. Immunology, p.361, New York, 1961. 7. Epstein, W. L., Skahen, J. R., Krasnobrod, H. J. invest. Dermat. 1962, 38, 223.
(1) The proportion of cases in tourists is increasing more rapidly than in the immigrant group (see table). (2) Most cases present within 2 months of arrival in this country although the spectrum spans 13 months. (3) Surprisingly, immigrants present earlier than tourists, with a median difference of 2.1 months in the incubation period between the two groups. The role of immunity in this area is unclear. (4) None of the malaria patients had taken adequate prophylaxis.
Distribution of cases of malaria imported from India, trend and time-series extrapolation for 1979. x-x-x=cases
recorded; 0
...
0
...
showing
0=time-series forecast
analysis was carried out to predict future The total anticipated for 1979 is 255 (see figure). If other factors do not change (e.g., the prevalence of P. vivax in the Punjab and immigration laws), the expected increase represents a considerable load on the laboratory and on clinical services. The routine workload is frequently disrupted by urgent examination of suspected cases to exclude P. falciparum. Other hospitals’serving comparable Asian immigrant groups can anticipate similar increases. Clearly there is a need for medical education in the use of malaria prophylaxis in risk groups in the U.K. as well as abroad. A time-series
cases.
Department of Hæmatology, Hillingdon Hospital, Uxbridge, Middlesex; and Department of Statistics, Polytechnic of the South Bank,
RUTH WARWICK G. SWIMER
London SE1
R. P. BRITT