Cancer - Dangers in the Process of High Butadiene and Network Marketing

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1 Remarks on the cancer risk values of 1,3-butadiene (draft Dutch Health Council 2012) Author: Wil ten Berge Date: 19 January Introduction The Dutch Health Council (DHC) has issued a proposal for a health based calculated occupational cancer risk value for 1,3-butadiene. The proposal is mainly based on epidemiological information. Epidemiological information is necessary to estimate human risks in the proper order of magnitude. The exposure estimates in epidemiological studies are often not detailed enough to study the mode of action at different dose rates. Animal studies can be designed to explore the effect of dose rate on the severity of effects, but the outcome cannot always be extrapolated to man because of different toxicological endpoints between man and rodents. Findings in rodents might contribute to the confidence in the human risk estimates. My remarks concern 2 items: 1. The extrapolation from the findings of Cheng et al. (2007) to cancer risk estimates. 2. The influence of dose rate on the cancer risk values. This will be explained in the next parts of this note. Comment Wil ten Berge, page 1

2 2 Risk calculation for leukaemia by exposure to butadiene (DHC 2012) The basis for risk calculation by the Dutch Health Council is the study of Cheng et al. (2007). The increased risk was due to an increased rate of leukaemia by cumulative butadiene exposure expressed as ppm*years. The basis for the leukaemia mortality risk is the ICD-code from the 10 th revision, C81 to C96 (Dutch Health Council 2012, page 52, line 22-24). This seems not to be correct. Cheng et al. (2007) refer to the paper of Sathiakumar et al. (2005). The last authors refer to the leukaemia deaths, but not to Hodgkin disease, not to non-hodgkin lymphomas and not to multiple myelomas (ICD C81 through C90). Sathiakumar et al. (2005) made the following conclusion on a relation between 1,3-butadiene worker exposure and the mortality by Non-Hodgkin Lymphoma, multiple myeloma, and Hodgkin disease Quotation from discussion Sathiakumar et al (2005): There was no excess of NHL deaths among the overall study group. Small increases in NHL deaths occurred among subgroups (polymerisation, maintenance labour, and laboratories) having potentially high exposure to butadiene, styrene, and DMDTC, but none of these increases was large or statistically significant. Workers in coagulation, another area with potential high exposure to the monomers, had no excess of this form of cancer. NHL SMRs did not display any marked patterns by years since hire or years worked. Matanoski et al in an investigation that included many of the same subjects in our study, reported a positive association between styrene and NHL. However, their findings and that of the present study are inconsistent with other research. Notably, studies of occupational groups exposed to levels of styrene higher than those found in the synthetic rubber industry have not reported any consistent increase in NHL deaths or cases. Matanoski et al reported that multiple myeloma was associated with butadiene in a study that included many of the subjects in our study. Our analyses by work area/job group provided little support for a causal relation between synthetic rubber industry employment and multiple myeloma. The highest work area/job group specific SMR for multiple myeloma was for production labourers. Maintenance labourers had an SMR of 150, but this result was based on only seven observed and 4.7 expected deaths. Data on polymerisation, coagulation, and laboratory workers were sparse but did not suggest any positive associations. Divine and Hartman found slightly more than expected deaths from multiple myeloma among butadiene production workers, but like that study s results for leukaemia, the data on multiple myeloma were too sparse and too internally inconsistent to provide any substantial support for a causal interpretation. Hodgkin s disease was not strikingly increased in any specific work area. Our study included only 12 decedents with Hodgkin s disease. This number was too small for detailed analyses. Quotation end In order to calculate the risk for leukaemia for the general population, only the ICD-codes C91 through C97 should be used. In the year 2011 a number of men and women died in the Netherlands, of which 1266 by Leukaemias (C91 through C97). Without any butadiene exposure the lifetime risk of dying from leukaemia is %. The preferred relative risk estimate by butadiene exposure according to Cheng et al (2007) is exp(0.0003*cumulative ppm[butadiene]*years). Comment Wil ten Berge, page 2

3 The relative risk and the lifetime risk is increased by butadiene exposure of workers during the age 20 to 65 over the working period of 45 year. The age specific leukaemia death rate (ICD C91 through C97) of the age of 20 to 65 of the Dutch population of the year 2011 (life tables from the Central Bureau of Statistics NL) is multiplied with exp(0.0003*cumulative ppm[butadiene]*years), In this calculation the risk of peak exposures is not accounted for. It is only the cumulative exposure to butadiene (sum ppm*years), which is assumed to control the relative risk. Further attention is required for the RR-risk estimate after the last exposure. If the RR is maintained over the whole remaining life without exposure, the additional leukaemia mortalities are blown-up to high numbers. It might be a reasonable assumption, to decrease the final cumulative dose with 5% per year from the last exposure year (65) to age 85, so that the RR 20 years after the last exposure becomes equal to 1. If health damaging DNAcrosslinks have been developed during butadiene exposure, one might expect a biological effect within 20 year. Cessation of smoking reduces also the cancer risk many years later. The life table of the Dutch population from the year 2011 provides higher rates of leukaemia mortality than the previous 10 years ( ). So the number of estimated additional leukaemia deaths on the basis of the 2011 life table is a fairly worst case estimate. 2.1 Result of risk calculation On the basis of the age specific leukaemia rate of the Dutch population over the year 2011 and the preferred RR factor according to Cheng et al. (2007) it is estimated, that 85 additional leukaemia deaths will occur on one million workers by cumulative occupational exposure to 1 ppm during 45 years from age 20 to 65. Comment Wil ten Berge, page 3

4 3 Toxicological significance of peak exposures The impact of peak exposures on specific mortality is difficult to quantify in retrospective cohort mortality studies. The biological effect might be affected by intensity and duration of exposure, possibly further modified by age, years of hire, age of first exposure etc. However, there is some indirect evidence, that peak exposures may affect specific mortality. The importance of peak exposures is illustrated with the example below by means of a toxicokinetic analysis. Many PBPK-models of butadiene have been reviewed by the EPA (2002). The parameters for all models were in the same order of magnitude. Simulations of the peak level of the first metabolite of butadiene, vinyl oxirane in humans was made by using a recently developed generic PBPK-model (Jongeneelen et al. 2010). The biochemical parameters for humans were taken from Csanady et al (1992) and Bond et al (1994). The exposure is simulated for 8 hour exposure (3 ppm) and 7.5 minutes (180 ppm), which ends up into the same cumulative inhalation dose (24 ppm*hours). Although the total exposure dose is similar in both exposure scenarios, the peak level of the butadiene metabolites vinyl oxirane and diepoxybutane in venous blood is respectively 10 times and 2 times higher for 7.5 minutes than for 8 hours of exposure. This is shown in figure 1 and 2. This example shows, that dose rate has an impact on the peak level of the metabolites of butadiene, vinyl oxirane and diepoxybutane. There are many examples in toxicology, that dose rate is important. These examples are lacking for butadiene in humans. The only example that dose rate at similar cumulative inhaled dose increases the mortality by specific tumours in case of butadiene, follows from the observations on malignant lymphoma in the NTP stop exposure study of butadiene in mice (NTP, 1993). These observations are summarised in table 1. Cumulative exposure Mice, NTP 434 Duration weeks PPM butadiene Malignant lymphoma observations 8000 ppm*weeks / ppm*weeks / ppm*weeks / ppm*weeks /50 Table 1: Malignant lymphoma in mice, observed at end of study period (700 days). In this specific case the dose rate affected the incidence of malignant lymphoma in mice, where the cumulative dose was similar. Malignant lymphoma increased significantly by increasing the exposure level with a factor of 2, while reducing the exposure duration with a factor 2. So the dose in ppm*weeks were similar. These findings cannot be shown for other tumours in mice in the same NTP study, because of the early mortality due to malignant lymphoma in mice. So the incidence of lung carcinoma and of heart angiosarcoma in mice decrease with increasing butadiene levels, causing high incidence of malignant lymphoma and early mortality (ten Berge, 1999). This author analysed also the specific tumour rates for lung alveolar carcinoma, heart angiosarcoma and malignant lymphoma in mice. The Kaplan-Meier tumour probability appeared to be related to the concentration of butadiene to the power 2 to 3. There might be a Comment Wil ten Berge, page 4

5 simple explanation for these findings on the basis of chemical reaction kinetics. This explanation is a scientific speculation on the main mode of action. Diepoxybutane (DEB) is the most reactive metabolite of butadiene. It has been proven to occur in mice, rats and humans. The concentration of diepoxybutane in humans is 100 times lower than in mice (Swenberg et al. 2011, Boysen et al. 2012). Diepoxybutane forms crosslinks in DNA of mice and rats (Goggin et al. 2009, 2011). The question is how much DNA-crosslinks will result into a mutation causing chromosomal breaks with leukaemia mortality. On the basis of simple chemical kinetics it can be explained that: 1 DNA crosslink per DNA molecule is linearly related to the concentration DEB 2 DNA crosslinks per DNA molecule are related to the square power of DEB concentration. 3 DNA crosslinks per DNA molecule are related to the third power of DEB concentration. An increase in concentration of only a factor 2 or 3 may cause a huge difference in more than one crosslink per DNA molecule. This might explain the increase of malignant lymphoma in mice by increasing the dose rate with only a factor of 2. It might also explain the impact of HITs (High Intensity Tasks) on the leukaemia mortality in epidemiology studies on butadiene exposed workers. 3.1 Conclusions Vinyloxirane and diepoxybutane are reactive metabolites of butadiene. Peak exposures or continuous exposure at the same cumulative dose result into different reactive metabolite levels. Increasing the dose rate with only a factor 2, but keeping the cumulative exposure similar, resulted into a more than linear increase of malignant lymphoma in mice. Mice are not a good model for simulating specific mortality in men considering the limited detoxifying rate of butadiene metabolites and the different tumour types. Experimental animal studies are still useful for exploring the effect of dose rate on toxicological effects, while the cumulative dose is similar. One might conclude that peak exposures seem to be more effective than continuous low exposure. This might also apply to humans. Considering the cumulative continuous exposure of butadiene as effective dose in risk assessment and ignoring peak exposures (High Intensity Tasks), may result into a conservative risk estimate. Comment Wil ten Berge, page 5

6 Fig 1: Venous blood level in humans of vinyl oxirane is plotted against time in hours after the start of exposure to butadiene. The total exposure dose is 24 ppm*hours, applied in 7.5 minutes or over a period of 8 hours. There is a considerable difference in maximum venous blood level of vinyl oxirane. Fig 2: Venous blood level in humans of diepoxybutane is plotted against time in hours after the start of exposure to butadiene. The total exposure dose is 24 ppm*hours, applied in 7.5 minutes or over a period of 8 hours. There is a considerable difference in maximum venous blood level of diepoxybutane. Comment Wil ten Berge, page 6

7 4 References Bond JA, Csanady GA, Gargas ML, Guengerich FP, Leavens T, Medinsky MA, Recio L, ,3-Butadiene: linking metabolism, dosimetry, and mutation induction. Environ Health Perspect. 102 Suppl 9: Boysen G, Georgieva NI, Bordeerat NK, Sram RJ, Vacek P, Albertini RJ, Swenberg JA, Formation of 1,2:3,4-diepoxybutane-specific hemoglobin adducts in 1,3-butadiene exposed workers. Toxicol Sci. 125(1): Cheng H, Sathiakumar N, Graff J, Matthews R, Delzell E, ,3-Butadiene and leukemia among synthetic rubber industry workers: exposure-response relationships. Chem Biol Interact. 166(1-3): Csanády GA, Guengerich FP, Bond JA, Comparison of the biotransformation of 1,3- butadiene and its metabolite, butadiene monoepoxide, by hepatic and pulmonary tissues from humans, rats and mice. Carcinogenesis. 13(7): EPA, Health Assessment of 1,3-Butadiene (EPA/600/P-98/001F, October 2002). Goggin M, Sangaraju D, Walker VE, Wickliffe J, Swenberg JA, Tretyakova N, Persistence and repair of bifunctional DNA adducts in tissues of laboratory animals exposed to 1,3-butadiene by inhalation. Chem Res Toxicol. 24(6): Goggin M, Swenberg JA, Walker VE, Tretyakova N, Molecular dosimetry of 1,2,3,4- diepoxybutane-induced DNA-DNA cross-links in B6C3F1 mice and F344 rats exposed to 1,3-butadiene by inhalation. Cancer Res. 69(6): doi: / CAN Epub 2009 Mar 10. PubMed PMID: ; PubMed Central PMCID: PMC Jongeneelen FJ, Berge WF, A generic, cross-chemical predictive PBTK model with multiple entry routes running as application in MS Excel; design of the model and comparison of predictions with experimental results. Ann Occup Hyg. 55(8): NTP, National Toxicology Program. NTP Toxicology and Carcinogenesis Studies of 1,3-Butadiene (CAS No ) in B6C3F1 Mice (Inhalation Studies). Natl Toxicol Program Tech Rep Ser. 434: Sathiakumar N, Graff J, Macaluso M, Maldonado G, Matthews R, Delzell E, An updated study of mortality among North American synthetic rubber industry workers. Occup Environ Med. 62(12): Swenberg JA, Bordeerat NK, Boysen G, Carro S, Georgieva NI, Nakamura J, Troutman JM, Upton PB, Albertini RJ, Vacek PM, Walker VE, Sram RJ, Goggin M, Tretyakova N, ,3-Butadiene: Biomarkers and application to risk assessment. Chem Biol Interact. 192(1-2): Comment Wil ten Berge, page 7

8 Ten Berge WF, Kaplan-Meier tumor probability as a starting point for dose-response modeling provides accurate lifetime risk estimates from rodent carcinogenicity studies. Ann N Y Acad Sci. 1999;895: Comment Wil ten Berge, page 8