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Original article
Women’s occupational exposure to polycyclic aromatic hydrocarbons and risk of breast cancer
  1. Derrick G Lee1,2,
  2. Igor Burstyn3,4,
  3. Agnes S Lai1,
  4. Anne Grundy5,6,
  5. Melissa C Friesen7,
  6. Kristan J Aronson8,9,
  7. John J Spinelli10,11
  1. 1Cancer Control Research, BC Cancer, Vancouver, British Columbia, Canada
  2. 2Department of Mathematics, Statistics, and Computer Science, St. Francis Xavier University, Antigonish, Nova Scotia, Canada
  3. 3Department of Environmental and Occupational Health, Dornsife School of Public Health, Drexel University, Philadelphia, Pennsylvania, USA
  4. 4Department of Epidemiology and Biostatistics, Dornsife School of Public Health, Drexel University, Philadelphia, Pennsylvania, USA
  5. 5University of Montreal Hospital Research Center (CRCHUM), Montreal, Quebec, Canada
  6. 6Department of Social and Preventive Medicine, Université de Montréal, Montréal, Québec, Canada
  7. 7Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
  8. 8Department of Public Health Sciences, Queen’s University, Kingston, Ontario, Canada
  9. 9Division of Cancer Care and Epidemiology, Cancer Research Institute, Queen’s University, Kingston, Ontario, Canada
  10. 10Population Oncology, BC Cancer, Vancouver, British Columbia, Canada
  11. 11School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada
  1. Correspondence to Dr Derrick G Lee, Department of Mathematics, Statistics, and Computer Science, St. Francis Xavier University, NS B2G 2W5, Canada; dlee{at}stfx.ca

Abstract

Objective To estimate the association between occupational polycyclic aromatic hydrocarbon (PAH) exposure and female breast cancer.

Methods Lifetime work histories for 1130 cases and 1169 controls from British Columbia and Ontario (Canada) were assessed for PAH exposure using a job-exposure matrix based on compliance measurements obtained during US Occupational Safety and Health Administration workplace safety inspections.

Results Exposure to any level of PAHs was associated with an increased risk of breast cancer (OR=1.32, 95% CI: 1.10 to 1.59), as was duration at high PAH exposure (for >7.4 years: OR=1.45, 95% CI: 1.10 to 1.91; ptrend=0.01), compared with women who were never exposed. Increased risk of breast cancer was most strongly associated with prolonged duration at high occupational PAH exposure among women with a family history of breast cancer (for >7.4 years: OR=2.79, 95% CI: 1.25 to 6.24; ptrend<0.01).

Conclusions Our study suggests that prolonged occupational exposure to PAH may increase breast cancer risk, especially among women with a family history of breast cancer.

  • cancer
  • exposure assessment
  • polyaromatic hydrocarbons (pahs)
  • epidemiology
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Key messages

What is already known about this subject?

  • Polycyclic aromatic hydrocarbons (PAHs) are a group of environmental pollutants, many of which are considered carcinogenic, and are associated with multiple cancer sites.

  • Although PAH exposure can play a role in development of female breast cancer, few studies have explored the risk from occupational exposures to PAHs.

What are the new findings?

  • This study found that women exposed to occupational PAH had a higher risk of developing breast cancer, and that the risk was related to the probability and duration of exposure.

  • These results provide additional evidence that women need to avoid exposure to PAHs in the workplace, and consider their working conditions, especially if they have a family history of breast cancer.

How might this impact on policy or clinical practice in the foreseeable future?

  • Given the implications of the study relate to workplace safety, the findings may affect safety standards, practices and policies.

  • Through knowledge translation, public awareness of the consequences of prolonged employment in industries with this potential exposure may influence a women’s work practices and the need for breast screening, especially if she has a family history of breast cancer.

Introduction

Polycyclic aromatic hydrocarbons (PAHs) are a large group of chemical compounds formed as by-products of combustion involving organic matter and are common environmental pollutants. Exposure to PAHs occurs through several sources including diet, air pollution and smoking.1 Low-level environmental PAH exposure is ubiquitous, but differences in PAH exposure can be influenced by more intense occupational exposures.1 2 Experimental studies show that metabolic activation of PAH to carcinogenic metabolites, including diol-epoxides and quinones,3–5 is mediated by enzymes that exist in all tissues.5–8 Mammary tissues bioaccumulate PAHs,2 9 10 thereby creating a potential concentration of PAH-derived carcinogens that may contribute to increased risk of breast cancer.

The association of PAH exposure and risk of female breast cancer remains unclear. Recent studies examining air pollution exposure and breast cancer risk reported mixed results, one with no association,11 while the other found a positive association.12 However, the majority of studies to date focused on ambient air pollution, smoking and other sources that confer exposure that is, compared with PAH-contaminated workplaces,13–18 much lower in intensity. Three studies that investigated the association of occupational PAH exposure and breast cancer observed an increased risk,19–21 including one that observed increased risk associated with early exposures, especially among women with certain tumour subtypes.21

Our objective was to evaluate the association between breast cancer among women employed in industries with PAH exposure, and to assess potential interactions with menopausal status, family history of breast cancer and other biological and socioeconomic factors, as well as examine tumour heterogeneity among cases. We hypothesise that accumulated occupational PAH exposure is a risk factor for breast cancer that may be further modified by a priori risk factors.

Methods

Study population

A multicentre, population-based case-control study of female breast cancer was conducted in the greater metropolitan area of Vancouver, British Columbia (BC) and Kingston, Ontario, between 2005 and 2010. The methodology is summarised below; more detailed information on the methods has been previously published.22

Greater Vancouver

Breast cancer cases were recruited from the province-wide, population-based BC Cancer Registry. Cases were women aged between 40 and 80 years, diagnosed with either in situ or invasive breast cancer, no cancer history except for non-melanoma skin cancer and were living in the cities of Vancouver, New Westminster, Richmond or Burnaby at the time of diagnoses. Controls were women recruited from the BC Cancer Breast Screening Programme, a population-based province-wide programme for the early detection of breast cancer, who consented to participate during routine screening mammography and were living in the same geographic areas. Controls were frequency-matched to cases by age in 5 year groups. Response rate among cases and controls were 54% (n=1001) and 57% (n=1014), respectively.

Kingston

Cases and controls were recruited from the Hotel Dieu Breast Assessment Programme in Kingston, Ontario. The breast assessment programme is part of the Ontario Breast Screening Programme that services Southeastern Ontario. Eligible participants were women under the age of 80 years with no cancer history except non-melanoma skin cancer, and not currently receiving cancer preventive drugs. Cases had a subsequent diagnosis of either in situ or invasive breast cancer, and controls had either normal mammography results or a diagnosis of benign breast disease. Controls were frequency-matched to cases by age in 5 year groups. Response rate among cases and controls were 59% (n=131) and 49% (n=164), respectively.

­

Due to minimum age restrictions for the BC Cancer Breast Screening, Ontario participants under 40 years of age were excluded, reducing the number of eligible participants from Kingston to 129 cases and 155 controls. Overall, a total of 1130 cases and 1169 controls were included in the analysis. Participants from both centres signed a consent form and completed the same questionnaire, which collected information relating to education, ethnicity, medical and reproductive history, lifetime tobacco consumption and lifetime occupational history. The questionnaire was either mailed and self-administered (n=726 cases, n=825 controls) or administered by telephone interview in English, Cantonese, Mandarin or Punjabi (n=404 cases, n=344 controls).

Occupational exposure assessment

Lifetime work history, which included start and end dates, industry, occupation and tasks performed for any job held for at least 6 months, was used to infer PAH exposure using a job exposure matrix (JEM) based on a statistical model23 of coal tar pitch volatiles (CTPV), a common PAH surrogate.2 Industries were classified using the North American Industry Classification System 2007 (Canadian edition) and occupations were classified using the Standard Occupation Classification 2010 (US edition). Industrial classification was done manually, while occupational classification was completed using an automated approach,24 which has previously been assessed for its reliability,25 and then manually reviewed by the authors (DGL, IB) to ensure accuracy. The JEM estimates the probability of job-specific exposure (τ) exceeding the permissible exposure level (PEL=0.2 mg/m3) for PAHs (θ=Pr(τ>PEL)). Jobs with ‘high’ exposure were defined as those with at least 9% probability of exceeding PEL and jobs with zero probability of exceedance were treated as unexposed. As the JEM evaluates the likelihood of exceeding the PEL, the unexposed referent group are those that did not receive high levels of PAH exposure, as opposed to never being exposed (see supplementary appendix).

Supplementary file 1

Two additional metrics, weighted duration of exposure and average probability of exposure weighted by duration, were also calculated for the analysis. Weighted duration is analogous to cumulative exposure, but substitutes probability for intensity, and average probability is ratio between weighted duration and total duration of employment (see Appendix). The number of years employed in each occupation was calculated and part-time work was adjustment to full-time equivalent duration based on a 40-hour work week. Duration and probability of exposure for all metrics were categorised based on tertiles among the controls.

Statistical analysis

Multivariable logistic regression was used to calculate adjusted ORs and 95% CIs to examine the relationship between occupational PAH exposure and breast cancer risk. To ensure that the referent group was truly unexposed when examining duration of medium and/or high risk of excess exposure, a nuisance variable: (1 if maximum risk of exposure level was low, 0 elsewhere) and (1 if maximum risk of exposure level was low or medium, 0 elsewhere) was used to adjust for low and/or medium risk of excess exposure, respectively. A priori confounders age (continuous), centre (Kingston vs Vancouver) and education, which was a surrogate for socioeconomic status (SES), were included in all models, and additional potential confounders were selected using an all-possible-model backwards selection procedure.26 Retention of a confounder occurred if it altered the OR for the ‘highest probability’ or ‘longest duration’ exposure levels by 10% or more. Potential confounders included ethnicity, self-reported body mass index (BMI), medical history (eg, use of oral contraceptives), menopausal status as defined by guidelines similar to Friedenreich et al,27 age of menarche, parity, age at first birth, age at first mammogram, first-degree family history of breast cancer, which was defined as having at least one immediate family member (eg, mother, sister or daughter) diagnosed with breast cancer, smoking status and pack-years of cigarettes.

To test for trends in exposure variables, exposure levels were treated as continuous variables (ie, none=0, low=1, medium=2 and high=3). Interactions with menopausal status, smoking (pack-years) and ethnicity were assessed through stratified analysis and interaction terms in the logistic models. Ethnicity was stratified as European versus Asian (Chinese, Japanese or Korean); all other ethnicities were excluded due to insufficient sample sizes. Supplemental analyses were conducted to estimate interactions with SES, based on education: undergraduate degree or higher versus community college or lower; BMI, normal weight and below versus overweight and above and first-degree family history of breast cancer. A case-case logistic model was used to evaluate whether PAH exposure-related breast cancer risk differed between hormone receptor positive (oestrogen receptor/progesterone receptor: +/–, –/+ or +/+) and negative (–/–) cases. Sensitivity analyses excluding BC cases not enrolled in the screening clinic that controls were recruited from (n=227), as well as restricting the statistical analysis to BC-only subjects (n=2015), were performed. All analyses were conducted using the statistical software R (V.3.4.4, R Foundation for Statistical Computing, Vienna, Austria).

Results

Cases were more likely to have ever been pregnant, and among parous women, cases were older at first pregnancy, had fewer subsequent pregnancies and did not breast feed as long as controls (table 1). Although cases were more likely to have ever been pregnant, the difference disappeared after adjustment for education and ethnicity. Cases tended to be older at time of first mammogram, and more likely to have a family history of breast cancer. Among current or previous smokers, cases experienced more pack-years. Controls were more likely of European descent, have a higher SES (ie, family income >$80 000, and/or received a graduate/professional school degree), have used oral contraceptives and were less likely to be overweight or obese.

Table 1

Descriptive statistics of the study population

Table 2 shows adjusted ORs from the logistic models for the various exposure metrics. Approximately 64% of participants were ever employed in an occupation with a non-zero probability of PAH exposure above the PEL (θ>0%), with about 40% ever employed in at least one occupation that was classified as a ‘high’ risk of receiving PAH exposure (θ≥9%). This is not surprising, as PAHs are by-products of combustion and the most common industry participants were employed in that was at risk for exposure was the food-service industry (see online supplementary table A1). Among cases, almost 70% were ever employed in an occupation with a non-zero probability of PAH exposure, compared with about 60% among controls, and approximately 44% of cases and 35% of controls were exposed to occupations with a ‘high’ risk of exceeding the PEL.

Table 2

Polycyclic aromatic hydrocarbon exposure and breast cancer risk based on variations of the job exposure matrices*

Exposure to ‘any’ level of PAHs was associated with an increased breast cancer risk (OR=1.32, 95% CI: 1.10 to 1.59). Elevated risk was also apparent for having ever been employed in a job with ‘high’ exposure (OR=1.43, 95% CI: 1.17 to 1.76). Duration at any level, at medium and/or high, and at high levels of PAH exposure were examined for possible dose-response relationship. Evidence of increased risk with duration was apparent for ‘medium or high’ exposure levels (the longest duration: OR=1.41, 95% CI: 1.10 to 1.81) and ‘high’ exposure levels (the longest duration: OR=1.45, 95% CI: 1.10 to 1.91), as well as elevated risk across each duration level; however, no evidence of a dose-response was apparent. Weighted duration and average probability both provided evidence of an elevated response to exposure (ptrend<0.01), with women in the longest duration category and the highest tertiles exhibiting increased risk for breast cancer, but no evidence of a dose-response relationship. Analyses involving only the a priori confounders (age, centre and education) yielded similar results, although the ORs were slightly inflated compared with the analysis with the final set of confounders. No differences were observed when continuous variables, such as age and BMI, were categorised in the statistical analyses.

There was no difference in the overall PAH-breast cancer association by menopausal status (p>0.2); however, among premenopausal women (table 3), for both ‘medium or high’ and ‘high’ exposure, there was a monotonic trend of increasing risk with prolonged duration (medium-high: OR=1.68, 95% CI: 1.12 to 2.52; high: OR=1.74, 95% CI: 1.10 to 2.74; all ptrend=0.01). Similarly, for weighted duration and average probability, the highest and the longest tertiles showed increased breast cancer risk (average probability: OR=1.50, 95% CI: 1.04 to 2.17, ptrend=0.02; weighted duration: OR=1.58, 95% CI: 1.08 to 2.29, ptrend<0.01) among premenopausal women.

Table 3

Polycyclic aromatic hydrocarbon exposure and breast cancer risk stratified by menopausal status*

A total of 844 cases were classified as hormone receptor positive and 166 as hormone receptor negative. No difference in breast cancer risk was observed by receptor status (case-case heterogeneity p>0.5). A sensitivity analysis that excluded cases not enrolled in the screening clinic that controls were recruited from yielded similar results as the full study. No differences were observed when stratifying by smoking status (never vs ever), ethnicity, SES or BMI (not shown). Family history was associated with an increased risk of breast cancer (table 4), especially among those with the longest duration at high PAH exposure (OR=2.79, 95% CI: 1.25 to 6.24), the longest weighted duration (OR=2.26, 95% CI: 1.19 to 4.28) and the highest level of average probability (upper tertile: OR=2.55, 95% CI: 1.34 to 4.84); all exposure metrics displayed increasing trends (all ptrend<0.01). Given that the majority of participants were from BC, a sensitivity analysis with the BC-only participants was performed; there were no important differences compared with the full study (data not shown).

Table 4

Exposure assessment to polycyclic aromatic hydrocarbons and breast cancer risk stratified by (first-degree) family history of breast cancer*

Discussion

The results provide evidence of increased risk of breast cancer associated with estimated occupational exposure to PAHs, especially among those with a family history. Breast cancer risk appeared higher among premenopausal women, based on the results from duration of exposure at high levels, weighted duration and average probability, but data do not support a measurable heterogeneity of effect. Differences in risk were not apparent by pathology subtype, including hormone receptor status, or by ethnicity, SES, BMI and smoking.

First-degree family history of breast cancer is known to double the absolute risk of breast cancer.28 Estimated effects PAH exposure on breast cancer risk were stronger among women with first-degree family history. Given the role genetics plays in the aetiology of breast cancer, there may be interactions between PAH exposure and genetic susceptibility. In particular, certain enzymes metabolise xenobiotic agents into procarcinogens6 8 and there is evidence of interactions between PAH-DNA adduct levels and metabolism-related genes29 30 that can elevate breast cancer risk.15

Similar to our results, Petralia et al19 observed elevated risks among premenopausal women with medium-to-high (average) probability of PAH exposure (OR=2.40, 95% CI: 0.91 to 6.01). Petralia et al reported no evidence of association with either cumulative exposure (analogous to our weighted duration), or duration of exposure; however, their results are not directly comparable to ours. Probabilities expressed by Petralia et al were ordinal categories representing the likelihood of PAH exposure, whereas our probabilities were continuous estimates that reflect the likelihood of excess PAH exposure, that is, above the PEL.

The hypothesised case-case interaction between PAH exposure and tumour oestrogen receptor status is based on evidence that PAHs are genotoxic and can damage DNA.5 PAH exposure can also trigger oestrogenic and anti-oestrogenic responses,31 which can increase the formation of quinones.5 The slightly stronger associations observed between PAH exposure and breast cancer risk among oestrogen receptor/progesterone receptor-positive cases are consistent with this idea, although our results could equally be due to chance.

Although all measured confounders were adjusted for in the models, the relatively low participation rate among both cases and controls, and the imbalances between case-control status in ethnicity and SES, could lead to biases that may impact the results in ways that are impossible to discern. However, as there is no reason to believe that responses rates would relate to PAH exposure at work, this issue would not bias the examination of our hypothesis. Comparisons between the two locations of the multicentre study, as well as a sensitivity analysis to discern the impact of the different sources for cases and controls in BC, yielded negligible differences from the full study, but selection biases may be operating in this study. Lastly, although participants reported lifetime work history retrospectively, it is highly unlikely that recall bias plays a role in this analysis since women were unaware of the specific exposure of interest.

Implementing a JEM derived from workplace measurements is a major strength of our study. Although others have used ‘industry’ to assess PAH exposure,32 33 JEMs that identify risks associated with specific occupations are better at capturing interpersonal variation in exposure.34 Expert-based JEMs are based solely on expert opinion, and are therefore assured to be imperfect, leading to misclassification. For example, the food-service industry, which employed >20% of participants during their respective careers, has a high risk of PAH exposure.23 The measurement-based JEM estimated the likelihood of exposure above PEL to be between 44%–88% depending on occupation, while two expert-based JEMs used for comparative purposes classified the majority occupations in the food-service industry as low risk or no exposure. Moreover, as opposed to ordinal rankings of previous or older exposure metrics, measurement-based JEMs provide quantifiable estimates that are less arbitrary, more easily interpretable and are based on empirical evidence rather than potentially biased opinions. Furthermore, using older JEMs may not be applicable to female workers, as the majority of the industries studied (eg, aluminium smelting) were male-dominated. Additionally, a measurement-based JEM can be updated as data become available. This flexibility is important because analytical methods for determining CTPV levels (eg, HPLC) have changed during the 30-year span of the database, and therefore exceedance risk could be time-dependent; previous analyses of the OSHA data for PAHs found no temporal effect.23 However, measurements have limitations, including using CTPV as a surrogate for PAHs. Sources for PAHs are a complex mixture and identifying the exact PAH or the toxicological effect is difficult, especially given their varying toxic equivalency (eg, benzo[α]pyrene is more toxic than chrysene). This measurement-based JEM is estimating a surrogate (eg, job in place of actual measurement) of a surrogate (eg, CTPV in place of PAHs), and therefore misclassification would occur if the ratio of total PAHs to CTPV differs substantially among occupations. The use of non-random measurements is another potential limitation, as the choice of when (ie, programmed or surprise inspections) to measure may bias the results; OSHA inspections are determined by responses to employee complaints, community concerns and reports of incidents. Use of compliance data from regulatory agencies, which may result in bias towards more inspections/measurements of premises suspected of being offenders, may also result in overestimation of exposures. However, analyses of one of the two OSHA databanks found that detected concentrations for 219 000 measurements were similar for surprise and programmed inspections.35 The anchoring of our JEM in measurements and the probability of exceeding workplace exposure limits is among the strengths of the innovative approach to exposure assessment that we adopted. Although the JEM was built on data from OSHA, a US governmental agency, and applied to a population of Canadian women, given that the two countries are closely related and the industrial safety standards are quite similar, exposures were assumed comparable. The JEM determined the probability of exceeding the PEL, and therefore there exists the possibility that the estimates are misclassified with respect to individual exposures; however, this is a universal limitation of JEMs. The modification of exposure assessment based on reported tasks (see Appendix) may lead to possible overestimation of exposure, as it shifts a zero probability to an imputed value; however, updates were based on tasks and materials handled that are known sources of PAHs; supplemental analyses showed that exclusion of the updated exposure assessments had no measurable impact on the results.

Differential misclassification is another limitation of using JEMs to classify exposure status, and can arise from dichotomising imperfectly assessed exposure when true exposure and the outcome are related, even in situations where the error in exposure is non-differential with respect to the outcome.36 All JEMs assign exposure at the group level that involves a mixture of truly exposed and unexposed individuals, which can produce complex biases.37 However, given the varying thresholds and indices used to define ‘exposed’, there is some assurance that the association between occupational PAH exposure and breast cancer, or at least among women with a family history of breast cancer, is not due to chance.

Tobacco smoke is a known source of PAH exposure, with some studies suggesting that long duration of smoking can increase breast cancer risk among women.17 18 In our study, we observed non-significant increased risk of breast cancer from smoking (pack-years), and similar risks from PAH exposure across smoking strata: smokers and non-smokers. However, it may not be appropriate to directly compare risks from occupational and non-occupational PAH sources (eg, smoking and diet). Different PAH sources result in complex mixtures of PAHs and other compounds that can alter the toxicity of the mixture as a whole. As such, identifying risk posed by individual PAHs is near impossible in epidemiological research.

In summary, PAH exposure was assessed through a novel measurement-based JEM and associated with increased risk of breast cancer. Prolonged occupational exposure to PAHs in jobs with a measurable probability of exceeding the occupational exposure limit is associated with increased breast cancer risk, especially among those with a first-degree family history of breast cancer. There is also some evidence to suggest premenopausal women experience higher risks. The results of this study have implications for workplace safety, as working women should be made aware of the risks associated with prolonged employment in industries with PAH exposure.

Acknowledgments

The authors would like to thank Dr. Chris Bajdik for his contributions to the study. The authors would like to thank Dr. Linda Warren (Screening Mammography Program of BC), Dr. Philip Switzer (Greig Associates), Caroline Speers (Breast Cancer Outcomes Unit, BC Cancer Agency), Agnes Bauzon, Alegria Imperial, Betty Hall, Lina Hsu, Maria Andrews and Teresa Pavlin for their assistance with participant recruitment and data collection in Vancouver. The authors would like to thank Dr. Ross Walker, Dr. Ralph George, Celine Morissette, Jane Warner, Hilary Rimmer, Meghan Hamel and Annie Langley for assistance with participant recruitment and data collection in Kingston. The authors would also like to thank Dr. Jerome Lavoué for his contributions, as the JEM developed for this study was based on the statistical model that he developed with coauthors DGL, IB and JJS.

References

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Footnotes

  • Contributors DGL designed the exposure assessment tool, cleaned and performed the statistical analysis of the data and drafted and revised the paper. IB helped design the exposure assessment tool with DGL, co-wrote the statistical analysis plan, assisted the statistical analysis and helped draft and revise the paper. ASL was responsible for the majority of the data collection, monitored data collection for the whole study and revised the paper. AG helped clean and analyse the data, and revised the paper. MCF assisted the statistical analysis and revised the paper. KJA is one the co-PI of the study, co-designed the study with JJS, co-wrote the statistical analysis plan with JJS and IB, ran the Ontario study centre and helped draft and revise the paper. JJS is one the co-PI of the study, co-designed the study with KJA, co-wrote the statistical analysis plan with KJA and IB, ran the BC study centre, assisted the statistical analysis and helped draft and revise the paper.

  • Funding Funding for this study was provided by a grant from the Canadian Institutes of Health Research (Funding Reference #: 69036). MCF was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health.

  • Competing interests None declared.

  • Patient consent Not required.

  • Ethics approval University of British Columbia/BC Cancer Agency Research Ethics Board, Queen’s University Health Sciences Research Ethics Board.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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