On recent meta-analyses of exposure to glyphosate and risk of non-Hodgkin's lymphoma in humans.

PURPOSE: A recent meta-analysis of five case-control studies and one cohort study reported that exposure to glyphosate was associated with increased risk of non-Hodgkin's lymphoma (NHL). The meta-analysis was based on estimates of risk from the included studies at the highest reported exposure level obtained from analyses with the longest lag period. The extent to which the summary estimate depends upon the exposure definitions and assumed latency period is uncertain. METHODS: We carried out sensitivity analyses to determine how the definition of exposure and the choice of latency period affect the summary estimate from meta-analyses of the 6 studies included in the recent meta-analysis. We also conducted a meta-analysis of ever-exposure to glyphosate incorporating the most updated results from the case-control studies. RESULTS: The summary estimates of risk varied considerably depending on both the assumptions about exposure level and latency. Using the highest reported exposure levels, evidence of an association between glyphosate and NHL was strongest when estimates from analyses in the cohort study with a 20-year lag [RR = 1.41 (95% CI 1.13-1.76)] and a 15-year lag [RR = 1.25 (95% CI 1.01-1.25)] were included. In our meta-analysis of ever-exposure with no lag period, the summary relative risk with updated estimates was 1.05 (95% CI 0.87-1.28). CONCLUSION: The results of meta-analyses of glyphosate exposure and NHL risk depend on assumptions made about both exposure level and latency period. Our results for ever-exposure are consistent with those of two recent meta-analyses conducted using somewhat different study inclusion criteria.

Menthol and Nonmenthol Cigarette Smoking: All-Cause Deaths, Cardiovascular Disease Deaths, and Other Causes of Death Among Blacks and Whites.

BACKGROUND: In contrast to whites, black smokers prefer menthol cigarettes over nonmenthol cigarettes by a large margin and tend to have higher mortality from several smoking-related diseases than whites, raising the possibility that menthol cigarettes contribute to racial disparities in risk. Evidence for differential associations between menthol and nonmenthol cigarettes indicates lower cancer risk for menthol smokers, but for cardiovascular disease (CVD) mortality, evidence has been inconsistent. METHODS AND RESULTS: Cox proportional hazards models were used to compute hazard ratios and accompanying 95% confidence intervals for all-cause and CVD mortality for menthol compared with nonmenthol cigarette smokers among 65 600 participants in the Southern Community Cohort Study, an ongoing community-based cohort with the largest number of menthol smokers being traced. Among the 27 619 current cigarette smokers, 4224 died during follow-up, with 1130 deaths attributed to CVD. Both all-cause (hazard ratio=0.93; 95% confidence interval=0.86-1.01; P=0.10) and CVD (hazard ratio=0.88; 95% confidence interval=0.76-1.03; P=0.10) mortality risks were similar in menthol compared with nonmenthol cigarette smokers. CONCLUSIONS: Smoking regardless of cigarette type is hazardous to health, but these results do not indicate that menthol cigarettes are associated with greater CVD risks than nonmenthol cigarettes.

Renal cell cancer among African Americans: an epidemiologic review.

Incidence rates for renal cell cancer, which accounts for 85% of kidney cancers, have been rising more rapidly among blacks than whites, almost entirely accounted for by an excess of localized disease. This excess dates back to the 1970s, despite less access among blacks to imaging procedures in the past. In contrast, mortality rates for this cancer have been virtually identical among blacks and whites since the early 1990s, despite the fact that nephrectomy rates, regardless of stage, are lower among blacks than among whites. These observations suggest that renal cell cancer may be a less aggressive tumor in blacks. We have reviewed the epidemiology of renal cell cancer, with emphasis on factors which may potentially play a role in the observed differences in incidence and mortality patterns of renal cell cancer among blacks and whites. To date, the factors most consistently, albeit modestly, associated with increased renal cell cancer risk in epidemiologic studies among whites--obesity, hypertension, cigarette smoking--likely account for less than half of these cancers, and there is virtually no epidemiologic evidence in the literature pertaining to their association with renal cell cancer among blacks. There is a long overdue need for detailed etiologic cohort and case-control studies of renal cell cancer among blacks, as they now represent the population at highest risk in the United States. In particular, investigation of the influence on renal cell cancer development of hypertension and chronic kidney disease, both of which occur substantially more frequently among blacks, is warranted, as well as investigations into the biology and natural history of this cancer among blacks.

Cancer among Scandinavian women with cosmetic breast implants: a pooled long-term follow-up study.

No increased risks of specific types of cancer following breast implantation have been consistently reported, but data on risk beyond 15 years are limited. We have pooled the results of 2 nationwide cohort studies of 3,486 Swedish and 2,736 Danish women who underwent cosmetic breast implantation between 1965 and 1993. Cancer incidence through 2002 was ascertained through nationwide cancer registries. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated to compare cancer incidence among women with implants with women in the general population. Mean duration of follow up was 16.6 years (range 0.1-37.8 years). Over 50% of women were followed for 15 years or more after breast implantation and 13.3% for at least 25 years. There was a reduced incidence of breast cancer (SIR=0.73; 95% CI 0.58-0.90), whereas lung cancer was above expectation (SIR=1.64; 95% CI 1.10-2.36). The increased risk of lung cancer is expected due to the high prevalence of smoking among the women with implants in our study. With respect to other site-specific cancers, no significantly increased or decreased SIR was observed. This study, which includes women followed for almost 4 decades, represents the longest follow up of women with cosmetic breast implants to date. The results provide no evidence of an association between breast implants and any type of cancer.

Fetal growth indicators and perfluorinated chemicals: a study in the Danish National Birth Cohort.

Perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS) are widespread persistent organic pollutants that have been associated with reduced birth weight at doses expected in many pregnant populations. The authors randomly selected 1,400 pregnant women and their newborns from the Danish National Birth Cohort (1996-2002) to investigate whether these compounds reduce organ growth. PFOS and PFOA were measured in maternal blood samples taken early in pregnancy. Placental weight, birth length, and head and abdominal circumferences were measured shortly after birth by trained midwives or nurses. Maternal PFOA levels in early pregnancy were associated with smaller abdominal circumference and birth length. For each ng/ml increase in PFOA, birth length decreased by 0.069 cm (95% confidence interval: 0.024, 0.113) and abdominal circumference decreased by 0.059 cm (95% confidence interval: 0.012, 0.106). An inverse association was also observed between PFOA and placental weight and head circumference, and a positive association was observed with newborn ponderal index, but none of these associations was statistically significant. Maternal PFOS levels were not associated with any of the five fetal growth indicators. These findings suggest that fetal exposure to PFOA but not PFOS during organ development may affect the growth of organs and the skeleton.

On the International Agency for Research on Cancer classification of glyphosate as a probable human carcinogen.

The recent classification by International Agency for Research on Cancer (IARC) of the herbicide glyphosate as a probable human carcinogen has generated considerable discussion. The classification is at variance with evaluations of the carcinogenic potential of glyphosate by several national and international regulatory bodies. The basis for the IARC classification is examined under the assumptions that the IARC criteria are reasonable and that the body of scientific studies determined by IARC staff to be relevant to the evaluation of glyphosate by the Monograph Working Group is sufficiently complete. It is shown that the classification of glyphosate as a probable human carcinogen was the result of a flawed and incomplete summary of the experimental evidence evaluated by the Working Group. Rational and effective cancer prevention activities depend on scientifically sound and unbiased assessments of the carcinogenic potential of suspected agents. Implications of the erroneous classification of glyphosate with respect to the IARC Monograph Working Group deliberative process are discussed.

A nationwide study of connective tissue disease and other rheumatic conditions among Danish women with long-term cosmetic breast implantation.

PURPOSE: Numerous epidemiologic studies have demonstrated that breast implants are not associated with connective tissue diseases (CTDs). However, many CTDs are rare, and continued follow-up of women with breast implants is warranted. METHODS: We extended by 5 years the follow-up of our earlier population-based cohort study of Danish women with cosmetic breast implants (n = 2761) and comparison groups of women with other types of cosmetic surgery (n = 8807). All women were followed from January 1977 through December 2001. Hospitalization and outpatient data for CTD and ill-defined and other rheumatic conditions in the implant and comparison groups were compared with those in the general Danish population. Additionally, CTDs and fibromyalgia were confirmed through medical chart review, and direct comparisons of the breast implant cohort with the comparison cohort were performed. RESULTS: When compared with general population rates, CTDs were not statistically significantly elevated in either the implant or the comparison cohorts. However, unspecified rheumatism was similarly increased in the implant (standardized rate ratio = 1.9; 95% confidence interval = 1.6 to 2.2) and comparison (standardized rate ratio = 1.5; 95% confidence interval = 1.4 to 1.7) cohorts. In analyses of diagnoses validated by chart review, women with cosmetic breast implants compared with those having other types of plastic surgery or consultation for plastic surgery had no statistically significant excess for any specific confirmed CTD or combined CTDs (hazard ratio = 1.3; 95% CI = 0.9 to 1.9). In addition, there was no relation between breast implants and confirmed fibromyalgia (hazard ratio = 1.2; 95% CI = 0.6 to 2.1). CONCLUSIONS: This extension of our earlier cohort study further supports the consensus of epidemiologic research that breast implants are unrelated to the development of CTD.

Perfluorinated chemicals and fetal growth: a study within the Danish National Birth Cohort.

BACKGROUND: Perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA) are man-made, persistent organic pollutants widely spread throughout the environment and human populations. They have been found to interfere with fetal growth in some animal models, but whether a similar effect is seen in humans is uncertain. OBJECTIVES: We investigated the association between plasma levels of PFOS and PFOA in pregnant women and their infants' birth weight and length of gestation. METHODS: We randomly selected 1,400 women and their infants from the Danish National Birth Cohort among those who completed all four computer-assisted telephone interviews, provided the first blood samples between gestational weeks 4 and 14, and who gave birth to a single live-born child without congenital malformation. PFOS and PFOA were measured by high performance liquid chromatography-tandem mass spectrometer. RESULTS: PFOS and PFOA levels in maternal plasma were on average 35.3 and 5.6 ng/mL, respectively. Only PFOA levels were inversely associated with birth weight (adjusted beta = -10.63 g; 95% confidence interval, -20.79 to -0.47 g). Neither maternal PFOS nor PFOA levels were consistently associated with the risk for preterm birth or low birth weight. We observed no adverse effects for maternal PFOS or PFOA levels on small for gestational age. CONCLUSION: Our nationwide cohort data suggest an inverse association between maternal plasma PFOA levels and birth weight. Because of widespread exposure to these chemicals, our findings may be of potential public health concern.

Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma: an extended follow-up.

PURPOSE: Many children diagnosed with retinoblastoma (Rb) survive into adulthood and are prone to subsequent cancers, particularly hereditary patients, who have germline Rb-1 mutations. We have extended the follow-up of a large cohort of Rb patients for 7 more years to provide new information on the risk of additional cancers after radiotherapy in long-term survivors. PATIENTS AND METHODS: We analyzed the risk of new cancers through 2000 in 1,601 Rb survivors, diagnosed from 1914 to 1984, at two US medical centers. The standardized incidence ratio (SIR) was calculated as the ratio of the observed number of cancers after hereditary and nonhereditary Rb to the expected number from the Connecticut Tumor Registry. The cumulative incidence of a new cancer after hereditary and nonhereditary Rb and radiotherapy was calculated with adjustment for competing risk of death. RESULTS: Subsequent cancer risk in 963 hereditary patients (SIR, 19; 95% CI, 16 to 21) exceeded the risk in 638 nonhereditary Rb patients (SIR, 1.2; 95% CI, 0.7 to 2.0). Radiation further increased the risk of another cancer in hereditary patients by 3.1-fold (95% CI, 2.0 to 5.3). Hereditary patients continued to be at significantly increased risk for sarcomas, melanoma, and cancers of the brain and nasal cavities. The cumulative incidence for developing a new cancer at 50 years after diagnosis of Rb was 36% (95% CI, 31% to 41%) for hereditary and 5.7% (95% CI, 2.4% to 11%) for nonhereditary patients. CONCLUSION: Hereditary Rb predisposes to a variety of new cancers over time, with radiotherapy further enhancing the risk of tumors arising in the radiation field.

A comparison of trends in the incidence of hepatocellular carcinoma and intrahepatic cholangiocarcinoma in the United States.

The incidence rates of liver cancers, both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), are increasing in the U.S. It is possible that the increases are related to common exposures, and if so, similar trends in incidence by gender, age, ethnicity, and calendar period, might exist. To examine this hypothesis, age-specific trends in the incidence of HCC and ICC in the Surveillance, Epidemiology and End Results program (1976-2000) were examined by year of diagnosis and year of birth. Age-period-cohort models were also fit to the data. The incidence of HCC in the most recent time period was twice as high among Black men (8.8/100,000) and women (2.6/100,000) as among White men (4.6/100,000) and women (1.2/100,000). However, between 1976 and 2000, incidence among all four ethnic- and gender-specific groups increased by >90% (White males, 123.2%; White females, 96.8%; Black males, 97.9%; Black females, 91.9%) with young White men experiencing the greatest increases (432%). In contrast, ICC rates were similar for Black (0.93/100,000) and White men (0.92/100,000), but higher for White (0.57/100,000) than Black women (0.39/100,000). Although ICC incidence increased among all groups, the increase was greatest for Black men (138.5%), followed by White men (124.4%), White women (111.1%), and Black women (85.7%) Age-period-cohort analyses of HCC revealed a significant cohort effect among younger men (45-65 years old), but not older men (65-84 years old), suggesting possible differences in etiology. In conclusion, the rates of HCC and ICC approximately doubled between 1976 and 2000. Trends by age, gender, ethnicity, and birth cohort suggest that heterogeneity exists in the factors influencing these rates.

Tobacco use in adult long-term survivors of retinoblastoma.

A significant risk of lung cancer was identified among hereditary, but not nonhereditary, retinoblastoma (Rb) patients. Tobacco use was investigated to determine whether differences in smoking prevalence might explain the lung cancer excess and to characterize smoking patterns in adult survivors of Rb. Subjects were 441 hereditary and 395 nonhereditary 1-year survivors of Rb, age >or=18 years, who responded to a telephone survey about current health behavior, including tobacco use. Response rates were 76% for hereditary and 73% for nonhereditary survivors. We compared patterns and predictors of current tobacco use among hereditary and nonhereditary survivors with other childhood cancer survivor studies and the U.S. population. Hereditary Rb survivors currently smoke cigarettes significantly less frequently than nonhereditary survivors (16. 8% versus 24.3%), although among current smokers, age at smoking initiation (17 years old) and average cigarettes (1.5 packs) smoked daily are similar. Predictors of current and ever cigarette smoking include nonhereditary Rb, older age, being female, less education, and use of other tobacco products. Rb survivors smoke cigarettes significantly less than the U.S. population (rate ratio, 0.63; 95% confidence interval, 0.5-0.8 for males; rate ratio, 0.75; 95% confidence interval, 0.6-0.9 for females), but Rb survivors have comparable smoking rates with other childhood cancer survivors. Smoking did not account for the increased risk of lung cancer among hereditary Rb patients, and this may point to an enhanced sensitivity to the carcinogenic effects of tobacco. Adult survivors of Rb should be encouraged to stop smoking.

Epidemiologic aspects of renal cell carcinoma.

Renal cell cancer accounts for 2% of all new cancer cases worldwide. Incidence rates have been rising steadily around the world. In the United States, the rates have been rapidly increasing among black Americans, whose incidence rate has now surpassed that of white Americans. Cigarette smoking and obesity are the most consistently established causal risk factors, accounting for more than 20% and 30% of renal cell cancers, respectively. Hypertension, rather than antihypertensive drugs, appears to influence renal cell cancer development, although the mechanism is unknown. Analgesics have not been convincingly linked with renal cell cancer risk. In general, there appears to be a protective effect of fruit and vegetable consumption, although no particular component of diet has been clearly implicated. There are sporadic and inconsistent reports of occupations or occupational exposures being associated with this cancer. Epidemiologic studies are needed to identify reasons for the increasing incidence of renal cell cancer, with particular focus on why the incidence rate for black Americans has risen to significantly surpass that of white Americans.

Risk of hospitalization for myocardial infarction among users of rofecoxib, celecoxib, and other NSAIDs: a population-based case-control study.

BACKGROUND: It remains uncertain if the excess cardiovascular risk of rofecoxib and celecoxib reported in clinical trials is present in routine practice and whether the use of other nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) also carries an increased cardiovascular risk. We performed a population-based case-control study to examine the risk of myocardial infarction (MI) among users of various categories of nonaspirin NSAIDs. METHODS: Using data from hospital discharge registries in the counties of North Jutland, Viborg, and Aarhus, Denmark, and the Danish Civil Registration System, we identified 10,280 cases of first-time hospitalization for MI and 102,797 sex- and age-matched non-MI population controls. All prescriptions for nonaspirin NSAIDs filled before the date of admission for MI were identified using population-based prescription databases. Relative risk estimates for MI were adjusted for a history of cardiovascular disease, hypertension, diabetes mellitus, chronic bronchitis or emphysema, alcoholism, liver cirrhosis, upper gastrointestinal bleeding, rheumatoid arthritis, systemic lupus erythematosus and the use of high-dose aspirin, platelet inhibitors, insulin or oral hypoglycemic drugs, antihypertensive drugs, lipid-lowering drugs, oral anticoagulants, nitrates, penicillamine, gold, oral glucocorticoids, and hormone therapy before the date of admission for MI. RESULTS: Current users of rofecoxib had an elevated risk estimate for hospitalization for MI compared with nonusers of any category of nonaspirin NSAIDs (adjusted relative risk [ARR], 1.80; 95% confidence interval [CI], 1.47-2.21). Increased risk estimates were also found among current users of celecoxib (ARR, 1.25; 95% CI, 0.97-1.62), other cyclooxygenase-2 selective inhibitors (ARR, 1.45; 95% CI, 1.09-1.93), naproxen (ARR, 1.50; 95% CI, 0.99-2.29), and other conventional nonaspirin NSAIDs (ARR, 1.68; 95% CI, 1.52-1.85). The highest ARRs were found among new users of all examined drug categories. CONCLUSIONS: Current and new users of all classes of nonaspirin NSAIDs had elevated relative risk estimates for MI. Although the increased risk estimates may partly reflect unmeasured bias, they indicate the need for further examination of the cardiovascular safety of all nonaspirin NSAIDs.

DNA repair, dysplastic nevi, and sunlight sensitivity in the development of cutaneous malignant melanoma.

BACKGROUND: Exposure to UV radiation is associated with cutaneous malignant melanoma (CMM). In mammalian cells, UV radiation induces DNA damage that can be repaired by the nucleotide excision repair system. We designed this case-control study to determine whether DNA repair capacity (DRC) is associated with the risk of CMM and to identify risk factors that may interact biologically with DRC in the development of melanoma. METHODS: Global DRC was measured in lymphocytes with the host-cell reactivation assay. Data were analyzed by use of multiple regression models. All statistical tests were two-sided. RESULTS: DRC could be determined for 132 case patients with incident melanoma and for 145 age- and sex-matched control subjects. No statistically significant association between melanoma risk and DRC by itself was found (odds ratio [OR] = 1.0; 95% confidence interval [CI] = 0.6 to 1.7, adjusted for age, sex, lymphocyte viability, and sample storage time). DRC, however, strongly influenced CMM risk in individuals with a low tanning ability or dysplastic nevi. Individuals with a low tanning ability and a low DRC had a higher risk for CMM (OR = 8.6; 95% CI = 2.7 to 27.5) than individuals with a higher tanning ability and a high DRC. Likewise, individuals with dysplastic nevi and a low DRC had a higher relative risk (OR = 6.7; 95% CI = 2.4 to 18.6) than those lacking dysplastic nevi and having a high DRC. Subjects with dysplastic nevi and a high DRC had an intermediate risk. A likelihood-ratio test gave statistically significant interactions between DRC and tanning response (P =.001) and between DRC and dysplastic nevus status (P =.04), which were independently associated with CMM risk. CONCLUSIONS: DRC may modify the risk for melanoma in the presence of other strong risk factors, such as a low tanning ability and the presence of dysplastic nevi. The occurrence of melanoma in subjects without these risk factors appears to be independent of DRC.