All-cause and cause-specific mortality in a cohort of WTC-exposed and non-WTC-exposed firefighters.

OBJECTIVE: To compare mortality rates in World Trade Center (WTC)-exposed Fire Department of the City of New York (FDNY) firefighters with rates in similarly healthy, non-WTC-exposed/non-FDNY firefighters, and compare mortality in each firefighter cohort with the general population. METHODS: 10 786 male WTC-exposed FDNY firefighters and 8813 male non-WTC-exposed firefighters from other urban fire departments who were employed on 11 September 2001 were included in the analyses. Only WTC-exposed firefighters received health monitoring via the WTC Health Programme (WTCHP). Follow-up began 11 September 2001 and ended at the earlier of death date or 31 December 2016. Death data were obtained from the National Death Index and demographics from the fire departments. We estimated standardised mortality ratios (SMRs) in each firefighter cohort versus US males using demographic-specific US mortality rates. Poisson regression models estimated relative rates (RRs) of all-cause and cause-specific mortality in WTC-exposed versus non-WTC-exposed firefighters, controlling for age and race. RESULTS: Between 11 September 2001 and 31 December 2016, there were 261 deaths among WTC-exposed firefighters and 605 among non-WTC-exposed. Both cohorts had reduced all-cause mortality compared with US males (SMR (95% CI)=0.30 (0.26 to 0.34) and 0.60 (0.55 to 0.65) in WTC-exposed and non-WTC-exposed, respectively). WTC-exposed firefighters also had lower rates of all-cause mortality (RR=0.54, 95% CI=0.49 to 0.59) and cancer-specific, cardiovascular-specific and respiratory disease-specific mortality compared with non-WTC-exposed firefighters. CONCLUSION: Both firefighter cohorts had lower than expected all-cause mortality. Fifteen years post 11 September 2001, mortality was lower in WTC-exposed versus non-WTC-exposed firefighters. Lower mortality in the WTC-exposed suggests not just a healthy worker effect, but additional factors such as greater access to free health monitoring and treatment that they receive via the WTCHP.

Nonmalignant respiratory disease mortality in male Colorado Plateau uranium miners, 1960-2016.

BACKGROUND: To evaluate trends of nonmalignant respiratory disease (NMRD) mortality among US underground uranium miners on the Colorado Plateau, and to estimate the exposure-response association between cumulative radon progeny exposure and NMRD subtype mortality. METHODS: Standardized mortality ratios (SMRs) and excess relative rates per 100 working level months (excess relative rate [ERR]/100 WLM) were estimated in a cohort of 4021 male underground uranium miners who were followed from 1960 through 2016. RESULTS: We observed elevated SMRs for all NMRD subtypes. Silicosis had the largest SMR (n = 52, SMR = 41.4; 95% confidence interval [CI]: 30.9, 54.3), followed by other pneumoconiosis (n = 49, SMR = 39.6; 95% CI: 29.6, 52.3) and idiopathic pulmonary fibrosis (IPF) (n = 64, SMR = 4.77; 95% CI 3.67, 6.09). SMRs for silicosis increased with duration of employment; SMRs for IPF increased with duration of employment and calendar period. There was a positive association between cumulative radon exposure and silicosis with evidence of modification by smoking (ERR/100 WLM≥10 pack-years = 0.78; 95% CI: 0.05, 24.6 and ERR/100 WLM<10 pack-years = 0.01; 95% CI: -0.03, 0.52), as well as a small positive association between radon and IPF (ERR/100 WLM = 0.06, 95% CI: 0.00, 0.24); these associations were driven by workers with prior employment in hard rock mining. CONCLUSIONS: Uranium mining workers had excess NMRD mortality compared with the general population; this excess persisted throughout follow-up. Exposure-response analyses indicated a positive association between radon exposure and IPF and silicosis, but these analyses have limitations due to outcome misclassification and missing information on occupational co-exposures such as silica dust.

End-stage renal disease incidence in a cohort of US firefighters from San Francisco, Chicago, and Philadelphia.

BACKGROUND: Firefighters perform strenuous work in hot environments, which may increase their risk of chronic kidney disease. The purpose of this study was to evaluate the risk of end-stage renal disease (ESRD) and types of ESRD among a cohort of US firefighters compared to the US general population, and to examine exposure-response relationships. METHODS: ESRD from 1977 through 2014 was identified through linkage with Medicare data. ESRD incidence in the cohort compared to the US population was evaluated using life table analyses. Associations of all ESRD, systemic ESRD, hypertensive ESRD, and diabetic ESRD with exposure surrogates (exposed days, fire runs, and fire hours) were examined in Cox proportional hazards models adjusted for attained age (the time scale), race, birth date, fire department, and employment duration. RESULTS: The incidence of all ESRD was less than expected (standardized incidence ratio (SIR) = 0.79; 95% confidence interval = 0.69-0.89, observed = 247). SIRs for ESRD types were not significantly increased. Positive associations of all ESRD, systemic ESRD, and hypertensive ESRD with exposed days were observed: however, 95% confidence intervals included one. CONCLUSIONS: We found little evidence of increased risk of ESRD among this cohort of firefighters. Limitations included the inability to evaluate exposure-response relationships for some ESRD types due to small observed numbers, the limitations of the surrogates of exposure, and the lack of information on more sensitive outcome measures for potential kidney effects.

Lung Cancer Mortality and Styrene Exposure in the Reinforced-Plastics Boatbuilding Industry: Evaluation of Healthy Worker Survivor Bias.

The evidence for styrene's being a human lung carcinogen has been inconclusive. Occupational cohorts within the reinforced-plastics industry are an ideal population in which to study this association because of their relatively high levels of exposure to styrene and lack of concomitant exposures to other known carcinogens. However, healthy worker survivor bias (HWSB), where healthier workers stay employed longer and thus have higher exposure potential, is a likely source of confounding bias for exposure-response associations, in part due to styrene's acute effects. Through December 31, 2016, we studied a cohort of 5,163 boatbuilders exposed to styrene in Washington State who were employed between 1959 and 1978; prior regression analyses had demonstrated little evidence for an exposure-response relationship between styrene exposure and lung cancer mortality. Based on estimates of necessary components of HWSB, we found evidence for a potentially large HWSB. Using g-estimation of a structural nested model to account for HWSB, we estimated that 1 year of styrene exposure at more than 30 parts per million accelerated time to lung cancer death by 2.29 years (95% confidence interval: 1.53, 2.94). Our results suggest possibly strong HWSB in our small cohort and indicate that large, influential studies of styrene-exposed workers may suffer from similar biases, warranting a reassessment of the evidence of long-term health effects of styrene exposure.

Cancer incidence in World Trade Center-exposed and non-exposed male firefighters, as compared with the US adult male population: 2001-2016.

OBJECTIVE: To compare cancer incidence in Fire Department of the City of New York (FDNY) firefighters who worked at the World Trade Center (WTC) site to incidence in a population of non-WTC-exposed firefighters, the Career Firefighter Health Study (CFHS) cohort, and to compare rates from each firefighter cohort to rates in demographically similar US males. METHODS: FDNY (N=10 786) and CFHS (N=8813) cohorts included male firefighters who were active on 11 September 2001 (9/11) and were followed until death or 31 December 2016. Cases were identified from 15 state cancer registries. Poisson regression models assessed cancers in each group (FDNY and CFHS) versus US males, and associations between group and cancer rates; these models estimated standardised incidence ratios (SIRs) and adjusted relative rates (RRs), respectively. Secondary analyses assessed surveillance bias and smoking history. RESULTS: We identified 915 cancer cases in 841 FDNY firefighters and 1002 cases in 909 CFHS firefighters. FDNY had: higher rates for all cancers (RR=1.13; 95% CI 1.02 to 1.25), prostate (RR=1.39; 95% CI 1.19 to 1.63) and thyroid cancer (RR=2.53; 95% CI 1.37 to 4.70); younger median ages at diagnosis (55.6 vs 59.4; p<0.001, all cancers); and more cases with localised disease when compared with CFHS. Compared with US males, both firefighter cohorts had elevated SIRs for prostate cancer and melanoma. Control for surveillance bias in FDNY reduced most differences. CONCLUSIONS: Excess cancers occurred in WTC-exposed firefighters relative to each comparison group, which may partially be explained by heightened surveillance. Two decades post-9/11, clearer understanding of WTC-related risk requires extended follow-up and modelling studies (laboratory or animal based) to identify workplace exposures in all firefighters.

The World Trade Center Health Program: Twenty years of health effects research.

It has been 20 years since the devastating terrorist attacks on September 11, 2001. Thousands were injured or killed during the attacks and many more are at risk of adverse health stemming from physical, psychological, and emotional stressors born out of the attacks. Private, federal, state, and local resources were gathered soon after the attacks to address impacts to the community, including the health and well-being of both responders and survivors. Many of these efforts are now largely consolidated under the federally mandated World Trade Center (WTC) Health Program. This program provides medical monitoring and treatment of qualifying conditions among the 9/11-exposed population and supports related physical and mental health research. In this commentary, we describe the WTC Health Program, with emphasis on the health-effects research it has funded since inception in 2011. We describe sentinel research publications, and how science has impacted the program. We provide examples relating studies in this special issue to important roles in the WTC Health Program research agenda. Finally, we provide a perspective on future research needs.

The World Trade Center Health Program: Petitions for adding qualifying health conditions.

The federally mandated World Trade Center Health Program provides limited health benefits for qualifying health conditions related to the 9/11 terrorist attacks. A qualifying health condition is an illness or health condition for which the member's exposure to airborne toxins, any other hazard, or any other adverse condition resulting from the 9/11 terrorist attacks is considered substantially likely to be a significant factor in aggravating, contributing to, or causing the illness or health condition. These qualifying health conditions are listed in federal regulations. The regulations also provide a process for amending this list. This commentary describes the methods developed for adding health conditions to the list of qualifying health conditions and discusses changes to the list that have occurred during the Program's 2011-2020 period.

Risk of cancer associated with low-dose radiation exposure: comparison of results between the INWORKS nuclear workers study and the A-bomb survivors study.

The Life Span Study (LSS) of Japanese atomic bomb survivors has served as the primary basis for estimates of radiation-related disease risks that inform radiation protection standards. The long-term follow-up of radiation-monitored nuclear workers provides estimates of radiation-cancer associations that complement findings from the LSS. Here, a comparison of radiation-cancer mortality risk estimates derived from the LSS and INWORKS, a large international nuclear worker study, is presented. Restrictions were made, so that the two study populations were similar with respect to ages and periods of exposure, leading to selection of 45,625 A-bomb survivors and 259,350 nuclear workers. For solid cancer, excess relative rates (ERR) per gray (Gy) were 0.28 (90% CI 0.18; 0.38) in the LSS, and 0.29 (90% CI 0.07; 0.53) in INWORKS. A joint analysis of the data allowed for a formal assessment of heterogeneity of the ERR per Gy across the two studies (P = 0.909), with minimal evidence of curvature or of a modifying effect of attained age, age at exposure, or sex in either study. There was evidence in both cohorts of modification of the excess absolute risk (EAR) of solid cancer by attained age, with a trend of increasing EAR per Gy with attained age. For leukemia, under a simple linear model, the ERR per Gy was 2.75 (90% CI 1.73; 4.21) in the LSS and 3.15 (90% CI 1.12; 5.72) in INWORKS, with evidence of curvature in the association across the range of dose observed in the LSS but not in INWORKS; the EAR per Gy was 3.54 (90% CI 2.30; 5.05) in the LSS and 2.03 (90% CI 0.36; 4.07) in INWORKS. These findings from different study populations may help understanding of radiation risks, with INWORKS contributing information derived from cohorts of workers with protracted low dose-rate exposures.

Site-specific Solid Cancer Mortality After Exposure to Ionizing Radiation: A Cohort Study of Workers (INWORKS).

BACKGROUND: There is considerable scientific interest in associations between protracted low-dose exposure to ionizing radiation and the occurrence of specific types of cancer. METHODS: Associations between ionizing radiation and site-specific solid cancer mortality were examined among 308,297 nuclear workers employed in France, the United Kingdom, and the United States. Workers were monitored for external radiation exposure and follow-up encompassed 8.2 million person-years. Radiation-mortality associations were estimated using a maximum-likelihood method and using a Markov chain Monte Carlo method, the latter used to fit a hierarchical regression model to stabilize estimates of association. RESULTS: The analysis included 17,957 deaths attributable to solid cancer, the most common being lung, prostate, and colon cancer. Using a maximum-likelihood method to quantify associations between radiation dose- and site-specific cancer, we obtained positive point estimates for oral, esophagus, stomach, colon, rectum, pancreas, peritoneum, larynx, lung, pleura, bone and connective tissue, skin, ovary, testis, and thyroid cancer; in addition, we obtained negative point estimates for cancer of the liver and gallbladder, prostate, bladder, kidney, and brain. Most of these estimated coefficients exhibited substantial imprecision. Employing a hierarchical model for stabilization had little impact on the estimated associations for the most commonly observed outcomes, but for less frequent cancer types, the stabilized estimates tended to take less extreme values and have greater precision than estimates obtained without such stabilization. CONCLUSIONS: The results provide further evidence regarding associations between low-dose radiation exposure and cancer.

Occupational asthma risk from exposures to toluene diisocyanate: A review and risk assessment.

BACKGROUND: Toluene Diisocyanate (TDI) is a known respiratory sensitizer linked to occupational asthma (OA). To better manage worker risks, an appropriate characterization of the TDI-OA dose-risk relationship is needed. METHODS: The literature was reviewed for data suitable for dose-response modeling. Previous study data were fit to models to derive prospective occupational exposure limits (OELs), using benchmark dose (BMD) and low-dose extrapolation approaches. RESULTS: Data on eight TDI-exposed populations were suitable for analysis. There were 118 OA cases in a population contributing 13 590 person-years. The BMD-based OEL was 0.4 ppb. The OEL based on low-dose extrapolation to working lifetime extra risk of 1/1000 was 0.3 ppb. CONCLUSIONS: This study synthesized epidemiologic data to characterize the TDI-OA dose-risk relationship. This approach yielded prospective OEL estimates below recent recommendations by the American Conference of Governmental Industrial Hygienists, but given significant study limitations, this should be interpreted with caution. Confirmatory research is needed.

Cancer mortality update with an exposure response analysis among styrene-exposed workers in the reinforced plastics boatbuilding industry.

BACKGROUND: There is sparse and inconsistent evidence of an association between styrene exposure and cancer. METHODS: This study examines mortality patterns in a previously studied cohort of 5201 workers employed in two Washington boat-building facilities, extending follow-up 5 years. Standardized mortality ratios (SMR) were calculated using state rates as referent. Cox regression calculated rate ratios (RR) per year employed in styrene-exposed exposed jobs. RESULTS: No excess deaths from lymphohematopoietic cancers (LHCs) were observed (SMR: 0.99, 95%CI: 0.74-1.30) when compared to the referent population; however, the relative risk increased with duration of employment in internal analyses. Conversely, lung cancer mortality was significantly elevated (SMR: 1.24, 95%CI: 1.08-1.41), but there was no evidence of a dose-response relationship. CONCLUSION: We found evidence that occupational exposure to styrene was associated with increased LHC risk, while no such association was observed for lung cancer.

Examining temporal effects on cancer risk in the international nuclear workers' study.

The paper continues the series of publications from the International Nuclear Workers Study cohort that comprises 308,297 workers from France, the United Kingdom and the United States, providing 8.2 million person-years of observation from a combined follow-up period (at earliest 1944 to at latest 2005). These workers' external radiation exposures were primarily to photons, resulting in an estimated average career absorbed dose to the colon of 17.4 milligray. The association between cumulative ionizing radiation dose and cancer mortality was evaluated in general relative risk models that describe modification of the excess relative risk (ERR) per gray (Gy) by time since exposure and age at exposure. Methods analogous to a nested-case control study using conditional logistic regression of sampled risks sets were used. Outcomes included: all solid cancers, lung cancer, leukemias excluding chronic lymphocytic, acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma, Hodgkin lymphoma and non-Hodgkin lymphoma. Significant risk heterogeneity was evident in chronic myeloid leukemia with time since exposure, where we observed increased ERR per Gy estimates shortly after exposure (2-10 year) and again later (20-30 years). We observed delayed effects for acute myeloid leukemia although estimates were not statistically significant. Solid cancer excess risk was restricted to exposure at age 35+ years and also diminished for exposure 30 years prior to attained age. Persistent or late effects suggest additional follow-up may inform on lifetime risks. However, cautious interpretation of results is needed due to analytical limitations and a lack of confirmatory results from other studies.

Mortality in a combined cohort of uranium enrichment workers.

OBJECTIVE: To examine the patterns of cause-specific mortality and relationship between internal exposure to uranium and specific causes in a pooled cohort of 29,303 workers employed at three former uranium enrichment facilities in the United States with follow-up through 2011. METHODS: Cause-specific standardized mortality ratios (SMRs) for the full cohort were calculated with the U.S. population as referent. Internal comparison of the dose-response relation between selected outcomes and estimated organ doses was evaluated using regression models. RESULTS: External comparison with the U.S. population showed significantly lower SMRs in most diseases in the pooled cohort. Internal comparison showed positive associations of absorbed organ doses with multiple myeloma, and to a lesser degree with kidney cancer. CONCLUSION: In general, these gaseous diffusion plant workers had significantly lower SMRs than the U.S. POPULATION: The internal comparison however, showed associations between internal organ doses and diseases associated with uranium exposure in previous studies. Am. J. Ind. Med. 60:96-108, 2017. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Mortality among workers exposed to toluene diisocyanate in the US polyurethane foam industry: Update and exposure-response analyses.

BACKGROUND: Mortality among 4,545 toluene diisocyante (TDI)-exposed workers was updated through 2011. The primary outcome of interest was lung cancer. METHODS: Life table analyses, including internal analyses by exposure duration and cumulative TDI exposure, were conducted. RESULTS: Compared with the US population, all cause and all cancer mortality was increased. Lung cancer mortality was increased but was not associated with exposure duration or cumulative TDI exposure. In post hoc analyses, lung cancer mortality was associated with employment duration in finishing jobs, but not in finishing jobs involving cutting polyurethane foam. CONCLUSIONS: Dermal exposure, in contrast to inhalational exposure, to TDI is expected to be greater in finishing jobs and may play a role in the observed increase in lung cancer mortality. Limitations include the lack of smoking data, uncertainty in the exposure estimates, and exposure estimates that reflected inhalational exposure only. Am. J. Ind. Med. 59:630-643, 2016. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

A study update of mortality in workers at a phosphate fertilizer production facility.

OBJECTIVE: To evaluate the mortality experience among 3,199 workers employed 1951-1976 at a phosphate fertilizer production plant in central Florida with follow-up through 2011. METHODS: Cause-specific standardized mortality ratios (SMRs) for the full cohort were calculated with the U.S. population as referent. Lung cancer and leukemia risks were further analyzed using conditional logistic regression. RESULTS: The mortality due to all-causes (SMR = 1.07, 95% confidence interval [CI] 1.02-1.13, observed deaths [n] = 1,473), all-cancers (SMR = 1.16, 95%CI 1.06-1.28, n = 431), and a priori outcomes of interests including lung cancer (SMR = 1.32, 95%CI = 1.13-1.53, n = 168) and leukemia (SMR = 1.74, 95%CI = 1.11-2.62, n = 23) were statistically significantly elevated. Regression modeling on employment duration or estimated radiation scores did not show exposure-response relation with lung cancer or leukemia mortality. CONCLUSION: SMR results showed increased lung cancer and leukemia mortality in a full cohort of the phosphate fertilizer production facility. There was, however, no exposure-response relation observed among cases and matched controls.

Post-9/11 cancer incidence in World Trade Center-exposed New York City firefighters as compared to a pooled cohort of firefighters from San Francisco, Chicago and Philadelphia (9/11/2001-2009).

BACKGROUND: We previously reported a modest excess of cancer in World Trade Center (WTC)-exposed firefighters versus the general population. This study aimed to separate the potential carcinogenic effects of firefighting and WTC exposure by comparing to a cohort of non-WTC-exposed firefighters. METHODS: Relative rates (RRs) for all cancers combined and individual cancer subtypes from 9/11/2001 to 12/31/2009 were modeled using Poisson regression comparing 11,457 WTC-exposed firefighters to 8,220 urban non-WTC-exposed firefighters. RESULTS: Compared with non-WTC-exposed firefighters, there was no difference in the RR of all cancers combined for WTC-exposed firefighters (RR = 0.96, 95%CI: 0.83-1.12). Thyroid cancer was significantly elevated (RR = 3.82, 95%CI: 1.07-20.81) from 2001 to 2009; this was attenuated (RR = 3.43, 95%CI: 0.94-18.94) and non-significant when controlling for possible surveillance bias. Prostate cancer was elevated during the latter half (2005-2009; RR = 1.38, 95%CI: 1.01-1.88). CONCLUSIONS: Further follow-up is needed to assess the relationship between WTC exposure and cancers with longer latency periods. Am. J. Ind. Med. 59:722-730, 2016. © 2016 Wiley Periodicals, Inc.

Creation of a retrospective job-exposure matrix using surrogate measures of exposure for a cohort of US career firefighters from San Francisco, Chicago and Philadelphia.

OBJECTIVES: To construct a cohort-specific job-exposure matrix (JEM) using surrogate metrics of exposure for a cancer study on career firefighters from the Chicago, Philadelphia and San Francisco Fire Departments. METHODS: Departmental work history records, along with data on historical annual fire-runs and hours, were collected from 1950 to 2009 and coded into separate databases. These data were used to create a JEM based on standardised job titles and fire apparatus assignments using several surrogate exposure metrics to estimate firefighters' exposure to the combustion byproducts of fire. The metrics included duration of exposure (cumulative time with a standardised exposed job title and assignment), fire-runs (cumulative events of potential fire exposure) and time at fire (cumulative hours of potential fire exposure). RESULTS: The JEM consisted of 2298 unique job titles alongside 16,174 fire apparatus assignments from the three departments, which were collapsed into 15 standardised job titles and 15 standardised job assignments. Correlations were found between fire-runs and time at fires (Pearson coefficient=0.92), duration of exposure and time at fires (Pearson coefficient=0.85), and duration of exposure and fire-runs (Pearson coefficient=0.82). Total misclassification rates were found to be between 16-30% when using duration of employment as an exposure surrogate, which has been traditionally used in most epidemiological studies, compared with using the duration of exposure surrogate metric. CONCLUSIONS: The constructed JEM successfully differentiated firefighters based on gradient levels of potential exposure to the combustion byproducts of fire using multiple surrogate exposure metrics.

Exposure-response relationships for select cancer and non-cancer health outcomes in a cohort of U.S. firefighters from San Francisco, Chicago and Philadelphia (1950-2009).

OBJECTIVES: To examine exposure-response relationships between surrogates of firefighting exposure and select outcomes among previously studied US career firefighters. METHODS: Eight cancer and four non-cancer outcomes were examined using conditional logistic regression. Incidence density sampling was used to match each case to 200 controls on attained age. Days accrued in firefighting assignments (exposed-days), run totals (fire-runs) and run times (fire-hours) were used as exposure surrogates. HRs comparing 75th and 25th centiles of lagged cumulative exposures were calculated using loglinear, linear, log-quadratic, power and restricted cubic spline general relative risk models. Piecewise constant models were used to examine risk differences by time since exposure, age at exposure and calendar period. RESULTS: Among 19,309 male firefighters eligible for the study, there were 1333 cancer deaths and 2609 cancer incidence cases. Significant positive associations between fire-hours and lung cancer mortality and incidence were evident. A similar relation between leukaemia mortality and fire-runs was also found. The lung cancer associations were nearly linear in cumulative exposure, while the association with leukaemia mortality was attenuated at higher exposure levels and greater for recent exposures. Significant negative associations were evident for the exposure surrogates and colorectal and prostate cancers, suggesting a healthy worker survivor effect possibly enhanced by medical screening. CONCLUSIONS: Lung cancer and leukaemia mortality risks were modestly increasing with firefighter exposures. These findings add to evidence of a causal association between firefighting and cancer. Nevertheless, small effects merit cautious interpretation. We plan to continue to follow the occurrence of disease and injury in this cohort.

Modelling complex mixtures in epidemiologic analysis: additive versus relative measures for differential effectiveness.

OBJECTIVES: Mixed exposures are often combined into single exposure measures using weighting factors. This occurs for many complex mixtures in environmental and occupational epidemiology including multiple congeners, air pollutants and unique forms of ionising radiation, among others. METHODS: The weights used for combining exposures are most often determined from experimental animal and cellular research. However, evidence from observational research is necessary to support their use in risk analyses, since results from experimental research do not directly translate to observational epidemiology. RESULTS: Using simulated data, we show that ratio-based relative weights cannot be reliably estimated from observational research. As a solution to this problem, we propose an approach for estimating differences in effectiveness of distinct exposures based on their excess effectiveness compared with a reference exposure. CONCLUSIONS: This alternative is easy to calculate and provides reliable estimates of differences in effectiveness of distinct exposures. This is important to regulatory bodies using relative measures for policy decisions, as well as practicing epidemiologists conducting risk analyses.