1 Department of Epidemiology and Public Health, Yale School of Medicine, New Haven, CT.
2 Department of Epidemiology and Biostatistics, Europe Institute of Oncology, Milan, Italy.
3 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD.
4 Department of Pathology, Yale School of Medicine, New Haven, CT.
Received for publication April 24, 2003; accepted for publication July 31, 2003.
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
case-control studies; Connecticut; hair dyes; lymphoma, non-Hodgkin; risk factors; women
Abbreviations: Abbreviations: CI, confidence interval; OR, odds ratio; RCA, Rapid Case Ascertainment Shared Resource.
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Epidemiologic studies have linked hair-coloring product use to non-Hodgkins lymphoma risk, but the results have been inconclusive. Two population-based case-control studies (2, 3) suggested that the use of hair dye increases the risk of non-Hodgkins lymphoma. Using these results, Pearce and Bethwaite concluded in 1992 that "the environmental exposure which seems most likely to have contributed to the increase in non-Hodgkins lymphoma is that of hair dyes" (4, p. 5498s).
Two prospective follow-up studies, however, have reached different conclusions. A study by Grodstein et al. (5) found no overall association between hair dye use and risk of non-Hodgkins lymphoma among participants in the Nurses Health Study. Another study by Thun et al. (6) reported that permanent hair dye use in general was not associated with the risk of non-Hodgkins lymphoma, and while prolonged use of black hair dyes may increase the risk, the proportion of the disease that could be explained by dark dye use is small. A population-based case-control study by Holly et al. (7) in the San Francisco Bay Area also found no association between hair-coloring product use and the risk of non-Hodgkins lymphoma.
Earlier epidemiologic studies, however, have suffered several major limitations. In two prospective follow-up studies (5, 6), for example, women were asked only four or five questions related to their lifetime use of permanent hair dye products. Considering the complicated use patterns among hair dye users, hair dye use experience cannot be ascertained by asking only a few questions. As pointed out by Zahm et al. (3), cohort studies that ascertain exposure early in life and observed subjects over time without repeated assessment will underestimate lifetime use, since the history of hair dye use is affected by the age at interview.
Perhaps more importantly, the risk of non-Hodgkins lymphoma associated with hair-coloring product use may need to be examined by time period of use since the formulations of hair-coloring products have undergone tremendous change over the past 20 years. As recently reviewed by Corbett (8), after the publication in 1975 by Ames et al. (9) of their finding that a number of hair dye ingredients were mutagenic, the experimental studies by the US National Cancer Institute also showed a carcinogenic effect of some hair dye intermediates in rats and mice (10). In 1979, the US Food and Drug Administration, prompted by the positive National Cancer Institute findings, proposed to require a cancer-warning label on hair dyes containing potential carcinogenic material. According to Corbett, "The resulting concern, under the prevailing opinion that there was no safe dose for a carcinogen, caused manufacturers to reformulate all oxidative dye products during 19781982" (8, p. 132). This reformulation involved the replacement or elimination of some of the dyes that had been reported to produce tumors in National Cancer Institute bioassays (8). Thus, the significant changes in hair dye formulation have resulted in the discontinuation of some hair-coloring product formulations over the past 20 years (7).
This population-based case-control study conducted among Connecticut women was designed to further investigate the issue of hair-coloring product use and the risk of non-Hodgkins lymphoma by type of product used, by subtype of the disease, and by time period of use.
![]() |
MATERIALS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
To provide accurate and consistent histologic classification of the cases, we obtained pathology slides (or tissue blocks) for all cases from the pathology departments where the case was diagnosed. The specimens were reviewed by two study pathologists (S. F., G. T.) who are experienced in the diagnosis of lymphoma. The non-Hodgkins lymphoma cases were classified according to the Working Formulation by grade (low, intermediate, or high); by histologic type (diffuse or follicular); or by immunologic type (B cell or T cell).
Population-based controls with Connecticut addresses were recruited using either random digit dialing methods for those below the age of 65 years or Health Care Finance Administration files for those aged 65 years or above. The participation rate for the controls obtained by random digit dialing was 69 percent including the initial telephone screening, and for those obtained from Health Care Finance Administration files, it was 47 percent. Cases and controls were frequency matched by age (±5 years) by adjusting the number of controls randomly selected in each age stratum every few months.
Interviews
All procedures were performed in accordance with a protocol approved by the Human Investigations Committee at Yale and the Connecticut Department of Public Health. After approval by the hospitals and by each subjects physician (for cases), or following selection through random sampling (for controls), potential participants were approached by letter and then by phone. Those who agreed were interviewed by trained study interviewers at either the subjects home or a convenient location. A standardized, structured questionnaire was used to obtain information on the use of hair-coloring products and other major known or suspected risk factors that might confound the association between hair-coloring product use and risk of non-Hodgkins lymphoma.
Regarding the use of hair-coloring products, respondents were provided a long list of names of hair-coloring processes and asked whether they had used these products at any time in their lives. If their responses were affirmative, they were asked to provide information related to each period in which they had used a hair-coloring product, with a period defined as the continuous timeframe of use of the same type and color product (without specifying a minimum duration of each period). If either changed, it was considered to be another period. Specifically, for each period of hair dye use, subjects were asked to provide the type and color of the hair-coloring product used, age at first use, age when use stopped, the number of years of use, and the frequency of use per year during those years of reported use. The respondents were also asked their main reason for using a hair-coloring product, such as to cover gray or to change natural hair color. The study interviewers were trained to use pictures of hair product labels for the interview.
Information on other potential confounding factors, including menstrual and reproductive history, family cancer history, occupation, diet, and demographic factors, was also collected during the interview. Dietary information was collected using a scannable semiquantitative food frequency questionnaire developed and validated by the Fred Hutchinson Cancer Research Center.
Data analysis
The primary analyses involved comparisons of overall use of hair-coloring products and more specific types (permanent, semipermanent, and temporary) and colors (dark: black, red, and brown, or light: blonde) of hair-coloring product use between cases and controls. As reviewed previously, since the contents of hair-coloring products have changed dramatically since the 1980s (7), we stratified women who started using hair-coloring products before 1980 from women who started in 1980 or later.
Since some subjects reported using a particular type or color of hair dye across different periods of life, with varying frequencies in each period, the average frequency of use for a product was not necessarily representative of the use in any one period. Therefore, instead of calculating an average frequency of lifetime use, we calculated the total number of times that a specific type or color of hair dye product was used, similar to the approach of Koenig et al. (11). We calculated the number of times a specific type was used for each period by taking the product of years of use (duration) and frequency of yearly use and then summed the results over a subjects lifetime.
Unconditional logistic regression was used to estimate the association between hair-coloring product use and risk of non-Hodgkins lymphoma by histologic type, immunologic type, and tumor grade, and to control for potential confounders. The potential confounding variables included in the final model were age (<50, 5070, >70 years) and family history of non-Hodgkins lymphoma in first-degree relatives. Adjustments of other variables, such as race, level of education, tobacco smoking, alcohol consumption, dietary protein or fat intakes, and farming history, did not result in material changes for the observed association and, thus, were not included in the final model reported here. Odds ratios and 95 percent confidence intervals were calculated using PROC LOGISTIC in the SAS statistical software package (SAS Institute, Inc., Cary, North Carolina).
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
|
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Hair dyes and other constituents vary according to the type and the color of hair-coloring product (12, 13). Carcinogenic compounds can be found in both permanent and semipermanent products and in most color formulations, but they usually occur in greater concentrations in the dark color products than in the light color products (3). Compounds used in the formulation of permanent dyes may be used in semipermanent dyes, with the addition of an oxidizing agent. Studies show that some hair dye components become strongly mutagenic after oxidization by H2O2 (9). Thus, a higher risk of non-Hodgkins lymphoma associated with darker permanent hair-coloring products is biologically plausible.
As cited earlier, the formulations of hair-coloring products have changed dramatically over the past 20 years (7, 8). Some carcinogenic compounds have been removed from the components of hair-coloring products. An increased risk of non-Hodgkins lymphoma found only among women who started using the products before 1980, but not among women who began use after 1980, is consistent with these changes.
It should also be noted that an increased risk of non-Hodgkins lymphoma among users of permanent darker-color products, who started using the products before 1980, was seen in our study only among women who had used the products for more than 25 years (table 3). This may indicate that a period of at least 25 years of use is needed for hair dye use to increase non-Hodgkins lymphoma risk. If this were the case, users who started using hair dye products after 1980 in our study would have used the products for less than 25 years, and our study would not be able to find an association because subjects were still in their induction and latency periods. Thus, while it is tempting to conclude that the observed different association for the two time periods appears to be consistent with the change in carcinogen contents in hair dye products during the past two decades, there is still a possibility that women who started using the products after 1980 have not yet reached the minimum induction and latency period. Since the number of subjects who used hair dye after 1980 was in general smaller than that whose use was before 1980, it is possible that this observed difference could be due to chance. Future studies are clearly needed to address the issue.
Several strengths and potential limitations of the study design must be considered in interpreting our findings. First, in this relatively large population-based case-control study, we assessed hair dye use at the time of diagnosis of the disease, not years before the diagnosis when young women may not have begun their hair dye use; second, we asked detailed questions and used a long list of names of hair-coloring processes to capture all hair dye uses; third, we collected detailed information on the duration, frequency, and type and color of hair-coloring products used for each period of use, which allowed us to quantitatively evaluate the risk by the major characteristics of hair-coloring product uses. Information regarding the year of first use allowed evaluation of the effect of changes in the contents of hair-coloring products during the past 20 years. Finally, the standardized, structured questionnaires used in this study were administered through face-to-face interviews with the subjects; no surrogate interviewing was used, which minimized the potential for misclassification of exposure.
The section of the questionnaire used to collect information on hair-coloring product use in this study was developed by the Johns Hopkins University and Clairol Company; it was specifically designed to assess hair-coloring product use and the risk of non-Hodgkins lymphoma. Although we have no direct measures of validity in this study, other research relating hair dye use and risk of breast cancer (6, 1421), non-Hodgkins lymphoma (3, 5, 7), multiple myeloma (22, 23), leukemia (3), and bladder cancer (24) suggests that women generally are able to report hair-coloring product use characteristics (such as duration, timing, frequency, type, and color).
One limitation for this case-control study is the potential for recall bias resulting from self-report of lifetime hair-coloring product use. In a reliability study, Shore et al. (16) reported a correlation coefficient (r) of 0.86 for duration of hair dye use from two interviews 1 year apart, with virtually no difference for cases and controls. The correlation coefficient for frequency of use was 0.92. However, although the results may indicate that the hair-coloring product information collected through self-report was reliable, differential overreporting of hair-coloring product use among non-Hodgkins lymphoma patients may still occur if patients believe that hair-coloring product use or specific type (or color) of hair-coloring product may increase a persons non-Hodgkins lymphoma risk. The lack of association between overall hair-coloring product use or hair color products used after 1980 and non-Hodgkins lymphoma argues against recall bias as having a major role for the results of our study.
Another potential limitation of the study is the relatively low response rate from potentially eligible subjects. Selection bias, however, is unlikely to have played a major role in the observed associations since we found no overall association between hair-coloring product use and non-Hodgkins lymphoma risk when all cases and controls were considered. The observed association also differs by duration of use and total number of applications and varies by type, color of products used, and period of use.
The role of chance should also be considered when interpreting our findings. Although a sample size of 601 cases and more than 700 age-matched controls gives us sufficient power to examine the overall relation between hair-coloring product use and non-Hodgkins lymphoma risk, the statistical power to examine the relation by non-Hodgkins lymphoma subtype, by color and type of hair-coloring products used, and by time period of use may be still limited.
In summary, in this population-based case-control study, we found an increased risk of non-Hodgkins lymphoma among women who started using darker hair-coloring products before 1980 but not among women who started using the products after that. Future studies designed to collect similar exposure information are needed to determine whether our findings for hair dye use before 1980 are replicated in other populations.
![]() |
ACKNOWLEDGMENTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The authors thank the institutions that allowed access to diagnostic materials and pathology reports, including the following hospitals: Charlotte Hungerford Hospital, Danbury Hospital, Greenwich Hospital, Griffin Hospital, Hartford Hospital, Johnson Memorial Hospital, Middlesex Hospital, Lawrence and Memorial Hospital, New Britain General Hospital, Bradley Memorial Hospital, Norwalk Hospital, St. Francis Hospital and Medical Center, St. Marys Hospital, Hospital of St. Raphael, St. Vincents Medical Center, Stamford Hospital, William W. Backus Hospital, Waterbury Hospital, Yale-New Haven Hospital, Manchester Memorial Hospital, Rockville General Hospital, Bridgeport Hospital, Windham Hospital, Sharon Hospital, Milford Hospital, New Milford Hospital, Bristol Hospital, MidState Medical Center, and Day-Kimball Hospital. Certain data used in this study were obtained from the Connecticut Tumor Registry located in the Connecticut Department of Public Health. The authors assume full responsibility for analyses and interpretation of these data.
![]() |
NOTES |
---|
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|