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Re: Cancer Incidence in Denmark Following Exposure to Poliovirus Vaccine Contaminated With Simian Virus 40
Affiliations of authors: R. Puntoni, M. Ceppi, Environmental Epidemiology and Biostatistics Units, National Cancer Research Institute of Genoa, Italy; M. Puntoni, Biostatistics Unit, University and National Cancer Research Institute of Genoa, Italy.
Correspondence to: Riccardo Puntoni, PhD, Environmental Epidemiology and Biostatistics Units, National Cancer Research Institute of Genoa, Largo Rosanna Benzi 10, 16132 Genoa, Italy (e-mail: riccardo.puntoni{at}istge.it).
In a recent article, Engels et al. (1) analyzed cancer incidence in Danish birth cohorts that differed in their exposure to simian virus 40 (SV40)-contaminated poliovirus vaccine. Engels et al. also performed a subgroup analysis of cancer incidence in children who were aged 0–4 years before, during, and after the period of vaccine contamination. The authors concluded that SV40 exposure is not associated with an increased incidence of mesothelioma, intracranial tumor, ependymoma, choroid plexus tumor, non-Hodgkin’s lymphoma, or leukemia. However, in our opinion, an increased incidence of ependymoma related to SV40 exposure was observed, and the results for mesothelioma and osteosarcoma were inconclusive.
Because newborn animals are reported to be more susceptible to SV40 oncogenic effects than adult animals (2), we contrasted the reported crude incidence rates of ependymoma in the exposed-as-infants cohort (0.51) and the exposed-as-children cohort (0.35) and obtained a crude relative risk of developing ependymoma of 1.46 (95% confidence interval [CI] = 1.06 to 1.95; P = .02). Surprisingly, Engels et al. did not report this comparison. The fact that the relative risk was increased is further strengthened by the results of the subgroup analysis of ependymoma in children aged 0–4 years shown in Table 2 of the Engels et al. article (1) that reported a relative risk of 2.59 (95% CI = 1.36 to 4.92) for the exposed cohort versus the unexposed cohort. In addition, we also calculated the relative risk of developing ependymoma for the post-exposed cohort versus the unexposed cohort and found that it was 2.48 (95% CI = 1.84 to 3.27; P = .001).
Engels et al. (1) also evaluated ependymoma incidence by calendar year (Fig. 2 of their article). They reported that seven cases of ependymoma occurred in 1964, which was after the poliovirus vaccine was cleared of SV40 contamination, four of which occurred in children aged 0–1 years. The authors excluded the possibility that some of the seven cases observed in 1964 were associated with vaccination of the mother during pregnancy, which is a known possible risk factor (3). It is also important to point out that, in the analysis by calendar year from 1963 through 1966, some of the exposed children were counted as person-years (Fig. 1
) and as cases in the unexposed incidence rates. Indeed, seven cases of ependymoma observed in the exposed cohort were attributed to the post-exposed period (i.e., 1963–1966). Moreover, the trend in incidence rates observed by calendar year can be attributed to the effect of SV40-contaminated poliovirus vaccine, particularly if we take into consideration the necessary latency period. Hence, a role for SV40 in the observed increase in incidence of ependymoma, particularly for exposures in the first years of life or during pregnancy, may be hypothesized.
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For mesothelioma, the age of the unexposed cohorts during the follow-up period ranged from 0 to 33 years. Because it was impossible to compare cancer rates in the exposed and unexposed cohorts after 33 years of age, the authors should only affirm that incidence of mesothelioma in the first 33 years of life did not increase among the exposed cohorts with respect to the unexposed cohort. However, this neoplasm is extremely rare before age 40 years. For osteosarcoma, where the follow-up started in 1978, the ages of the exposed-as-child and the unexposed cohorts during the follow-up period were 26–51 years and 7–33 years, respectively. Similar to the general age limitations for occurrence of mesothelioma, osteosarcoma is extremely rare after age 25 years. In addition, the lack of incidence data in the period between 1962 and 1978 does not allow a definitive conclusion about possible increases in incidence in the years immediately after the vaccination period.
In summary, estimation of data not available (i.e., in the periods before and after the follow-up) through regression modeling, particularly in the period most relevant to cancer risk evaluation (i.e., 1962–1978), may bias risk estimation. Moreover, we believe that comparison of incidence rates among the available age strata is the best option for definitive assessment of cancer incidence in individuals exposed to SV40.
REFERENCES
1 Engels EA, Katki HA, Nielsen NM, Winther JF, Hjalgrim H, Gjerris F, et al. Cancer incidence in Denmark following exposure to poliovirus vaccine contaminated with simian virus 40. J Natl Cancer Inst 2003;95:532–9.
2 Girardi AJ, Sweet BH, Hilleman MR. Factors influencing tumor induction in hamsters by vacuolating virus, SV40. Proc Soc Exp Biol Med 1963;112:662–7.[Medline]
3 Heinonen OP, Shapiro S, Monson RR, Hartz SC, Rosenberg L, Slone D. Immunization during pregnancy against poliomyelitis and influenza in relation to childhood malignancy. Int J Epidemiol 1973;2:229–35.
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J Natl Cancer Inst 2003 95: 1553-1555.
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