From: Mack, ThomasTo: Vela, Monet@OEHHASubject: CIC peer review: listed chemicals in coffeeDate: Monday, July 2, 2018 4:56:16 PM

I have only two general comments about the documents1. Prop 65 does not address protection. While it is reasonable to mention the evidence that

coffee protects against some cancers, there is far too much emphasis, and protection isirrelevant to the CIC mandate (pertinent to regulation, not causation) The safety of coffee ispresumably a matter of dose, and the chemicals are listed as carcinogens. It is coffee that issafe, not coffee that is beneficial that should be the message. Certainly the review of studiesis interesting but out of place.

2. Being legalistic but the phraseology should always be that coffee is safe, and NOT that thechemicals in coffee are safe. If necessary, a phrase like “at the doses in coffee, the chemicalsare safe”, and the data reviewed should deal with dose-response, and studies of coffee perse that show (not benefit) but the absence of risk

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30 July 2018 

To  

Office of Environmental Health Hazard Assessment (OEHHA) 

Care of: Ms. Monet Vela 

PO Box 4010, MS‐23‐11F 

Sacramento, CA  95812‐4010 

 

From  

Thomas A. McDonald, MPH, PhD 

Carcinogen Identification Committee (CIC) Member 

4900 Johnson Drive 

Pleasanton, CA  94588 

 

Subject:  CIC Peer Review, Listed Chemicals in Coffee 

Per the request of OEHHA’s Chief Deputy Director Allan Hirsh  (June 22, 2018),  I am providing 

peer review comments as a member of the CIC on OEHHA’s proposed regulation that exposures 

to listed chemicals in coffee pose no significant risk of cancer.   

I have  reviewed OEHHA’s  Initial Statement of Reasons  for  the proposed  regulation  in §25704 

regarding coffee constituents.    I have also read the 2018  IARC Monograph 116 that reviewed 

the carcinogenicity of drinking coffee.  

I agree with the conclusion that drinking coffee does not result  in an overall  increased risk of 

cancer  in  the California population.      I  further agree with OEHHA’s proposed  regulation  that 

exposures  to  coffee  constituents  that  are  listed  on  Proposition  65  do  not  pose  a  significant 

cancer risk when consumed as coffee.  

 

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Joseph R. Landolph, Ph. D. Telephone: (626)-993-4397 (Cell) Norris Topping Tower, Room #4427A Telephone: (323)-44206908 (Office) USC/Norris Comprehensive Cancer Center E-mail: USC/Norris Comprehensive Cancer Center Joseph.Landolph@med.usc.edu Keck School of Medicine Health Sciences Campus University of Southern California Los Angeles, California 900389-9176 August 13, 2018 Ms. Monet Vela Office of Environmental Health Hazard Assessment P. O. Box 4010, MS-23-11-F Sacramento, California 95812-4010

Re: Peer-Review of the Initial Statement of Reasons (ISOR) For Whether Coffee Should be Listed as a Carcinogen or Not

Dear Ms. Vela (Monet),

Thank you very much for sending me a request to submit to you a peer review of

the Initial Statement of Reasons (ISOR) for whether coffee drinking should be listed as a chemical known to the State of California to cause cancer or not. I have carefully read over all the materials you have sent to me, and I have looked up some other materials on this issue myself. I have then prepared the requested peer review, which follows. Peer-Review of the Initial Statement of Reasons (ISOR), Title 27, California Code of Regulations, Adoption of New Section 25704, Exposures to Listed Chemicals in Coffee Posing No Significant Risk of Cancer. I. E., On Whether or Not Coffee Drinking Should be Listed as a Chemical Known to the State of California to Cause Cancer and Placed on the Proposition 65 List of Chemicals Known to the State of California to Cause Cancer or Developmental and Reproductive Toxicity. June, 2018. General Comments: In general, this ISOR on coffee roasting, brewing, and drinking and cancer is well-researched, well-written, very interesting, and makes the salient points that coffee contains many carcinogens, but also contains many anti-oxidants and anti-carcinogens. The authors made a thorough literature search, and identified a number of articles, including the IARC Volume 116, 2018 review, that covered over 1,000 studies of coffee for its carcinogenicity and anti-carcinogenicity. I quickly conducted an OVID Medline Search on my computer, and found 379 articles dealing with coffee and cancer, four of which I retrieved and cited in this review of this coffee ISOR. In my opinion, the authors came to the correct opinions and conclusions, namely, that while roasting,

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brewing, and drinking coffee leads to the consumption of many carcinogens, it also leads to the consumption of many anti-oxidants and anti-carcinogens (soluble and insoluble dietary fiber) in coffee that mitigate the carcinogenicity of the many carcinogens in coffee, apparently to negligible amounts, and also reduces the frequency of cancers in many organs in humans. In this reviewer’s opinion, the ISOR is acceptable for indicating the coffee drinking poses no significant risk of cancer. The authors did a great job of researching and writing this document, in my opinion. This document appropriately breaks the logjam between those who would list coffee as a carcinogen and those who would not list coffee as a carcinogen, decisively in favor of the latter. Specific comments analyzing each section of this document and making suggestions for improvements in the writing of this document follow. Summary This section reads very well in general. I suggest adding a small phrase to Page 3, para. 1, line 7, so that it reads as follows: “…brewing and drinking coffee pose no significant risk of cancer.” Page 3, para. 1, lines 11-12: I again suggest modifying this sentence as follows: “…other than the inherent processes of roasting coffee beans, brewing coffee, and drinking this coffee.” This should improve the clarity of the sentence. Background/Problem to be Addressed by the Proposed Rulemaking

A. Proposition 65 This section is also written reasonably well. Page 4, para. 2, lines 5-12: This is very interesting, that coffee contains “a number of carcinogens listed under Proposition 65 (e.g., acetaldehyde, acrylamide, benz(a)anthracene, benzo(b)fluoranthene, benzo(k)fluoranthene, benzo(a)pyrene, chrysene, dibenz(a,h)anthracene, formaldehyde, furan, furfuryl alcohol, indeno(1,2,3-cd)pyrene, 4-methylimidazole, naphthalene, and pyridine. It is also interestingly that coffee also contains numerous compounds that exhibit cancer chemo-preventive properties (e., g. free radical scavengers, antioxidants), as discussed below. Therefore, it is important to discuss briefly here why, since coffee contains many carcinogens, it is not carcinogenic when administered to humans by the drinking water route. What are the mechanisms of the carcinogenicity of this mixture of different classes of carcinogens? It is important set forth some hypotheses here, since litigants will try to sue coffee companies because coffee contains many carcinogens, at least 15 prominent examples of which are mentioned above, in particular, benzo(b)fluoranthene, benzo(k)fluoranthene, benzo(a)pyrene, dibenz-(a,h)anthracene, formaldehyde, furan, furfuryl alcohol, indeno(1,2,3-cd)pyrene, 4-methylimidazole, naphthalene, and pyridine. In

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particular, benzo(a)pyrene, dibenz(a,h)anthracene, benzo(k)fluoranthene, and benzo(b)fluoranthene have been studied for many years and found to be strong animal carcinogens, and are also thought to be strong human carcinogens. It could be hypothesized that 1) the carcinogenicity of all of these carcinogens in this mixture of carcinogens could be additive, 2) the carcinogenicity of all these different carcinogens could be synergistic (PAHs vs. 4-methylimidazole vs. formaldehyde vs. furan and furfuryl alcohol vs. pyridine, or 3) the carcinogenicity among the different groups could be antagonistic or competitive. 4) Another hypothesis that could be put forward is that the levels of these carcinogens are sufficiently small that the risk of carcinogenicity is low on the cancer risk vs. carcinogen dose, dose-response curve. It is likely that hypothesis #3 and #4 are operant here. Further, it may also be 5) that there is competition between the different classes of carcinogens in coffee and other non-carcinogens in coffee for metabolic activation by the cytochrome P450 enzyme system, and that thereby, the carcinogenicity of the mixture, coffee, is less than the sum of its carcinogenic parts. A combination of hypotheses #3, #4, and #5 is most likely. 6) In addition, the presence of cancer chemo-preventive chemicals in coffee such as free radical scavengers and anti-oxidants, may also act antagonistically toward the action of the carcinogens in coffee. Hence, hypotheses #3, #4, #5, and #6,together, may explain why coffee is not carcinogenic to humans who drink it. It has been notoriously difficult to predict the carcinogenicity of complex mixtures such as coffee due to the considerations detailed above. Hence, coffee needs to be considered a complex mixture. To date, according to IARC, Volume 116, 2018, it is either not carcinogenic or not classifiable according to its carcino- genicity.

B. IARC’s Findings on Coffee This section is well-researched, well-written, and very interesting. The authors found the relevant scientific literature and cited it appropriately. According to the Inter- national Agency for Research on Cancer (IARC), Volume 116, 2018, 1) after reviewing more than 1,000 studies of coffee and cancer, IARC concluded that there was inadequate evidence to for the carcinogenicity of drinking coffee, and IARC placed coffee in Group 3: “Not classifiable as to its carcinogenicity (IARC, 2018).” Further, the authors of the ISOR also noted that “IARC also found strong evidence in humans that coffee has anti- oxidant effects, effects that are related to reductions in cancer risk.” (IARC, Volume 116, 2018). Interestingly, “IARC concluded that drinking coffee is inversely associated with cancers of the liver and uterine endometrium (i. e., risk is reduced).“ (IARC, Volume 116, 2018). “IARC found moderate evidence of an inverse association between coffee drinking and colorectal adenoma” and “…no association or a statistically significant inverse association for coffee intake and breast cancer,” and that “there is evidence suggesting lack of carcinogenicity for cancers of the pancreas and prostate.” Further, “IARC also evaluated several long-term studies of the carcinogenicity of coffee in rats

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and mice, and concluded that these studies provided inadequate evidence for the carcinogenicity of coffee.” (IARC Volume 116, 2018). This reviewer agrees with all of these statements. Please also cite in this section one review I found, indicating that coffee consumption is not associated with ovarian cancer risk, in a dose-response meta-analysis of prospective cohort studies (RR = 1.06, 95% CI: 0.89-1.26). (Berretta et al, 2018). Please cite a second review that I found, indicating that three was not significant association observed with all-cause or cancer mortality, neither for caffeinated and decaffeinated coffee (Torres-Collado et al, European Journal of Nutrition, 2018). Please cite the following review, indicating that there is an association of coffee intake with risk of breast, endometrial, and ovarian cancer among Canadian women (Arthur, R., et al, Cancer Epidemiology, 2018). Please cite the following reference, indicating that there is an association of coffee, tea, and caffeine intake with risk of breast, endometrial, and ovarian cancer among Canadian women (Arthur, R., Kirsh, V. A., and Rohan, T. E., Cancer Epidemiology, 56: 75-82, 2018). These authors found that total coffee, caffeinated coffee, and caffeine intake were associated with lower risk of endometrial cancer. They also found that higher caffeinated coffee intake may be positively, but weakly, associated with risk of premenopausal breast cancer. Total/caffeinate coffee and caffeine may be positively associated with risk of breast cancer among normal weight women.

C. Implications of IARC’s Findings That Coffee Reduces the Risk of Certain Cancers.

This section is also well-researched, well-written, and interesting, and shows that, in general, coffee consumption is protective against colorectal cancer.

D. Coffee is a Complex Mixture of Carcinogens and Anti-Carcinogens It is fascinating that coffee, in addition to containing numerous strong carcinogens, also contains chemicals that have biological activities associated with protective anti-carcinogenic effects, including anti-oxidants and free radical scavengers [phenolic and polyphenolic compounds that scavenge free radicals] (chlorogenic acids and vitamin E), chemicals that increase the colon’s ability to move intestinal contents in a reduced amount of time (soluble and insoluble dietary fiber), reducing colorectal cancer risk, anti-inflammatory chemicals, and soluble and insoluble fiber that reduce the uptake of certain carcinogens into the body. This section is very well-researched, well-written, and details that coffee contains both carcinogens and anti-carcinogens. Please add the following sentence and reference to this section: “Coffee also contains caffeic acid, caffeine, chlorogenic acid, cafestol and Kahweol, anti-oxidants, anti-inflammatory compounds, immunomodulators, antimicrobials, neuroprotective

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compounds, cardio-protective agents, hepatoprotective agents, nephron-protective compounds, and anti-diabetic agents (Islam et al, 2018).

E. Exposure to Carcinogens in Coffee Produced by and Inherent in the Processes of Roasting and Brewing Coffee Does Not Pose a Significant Cancer Risk.

This is an excellent concluding section. It sums up nicely that “Coffee….. shows reduction in cancers in certain humans, has not been shown to increase any cancers, and is particularly rich in cancer-chemo-preventive compounds.” This is an excellent summation. This reviewer suggest that you write, “Coffee drinking… shows…” The concluding sentence that, “Considering the reductions of specific cancers resulting from coffee drinking, the rich mix of cancer-preventative agents in brewed coffee, and the lack of evidence showing increases in cancer, OEHHA has determined that exposure to listed carcinogens in coffee that are produced as part of and inherent in the processes of roasting and brewing coffee does not pose a significant cancer risk under Proposition 65.” This is an excellent concluding sentence, and I agree with it. References Arthur, R., Kidrsh, V. A., and Rohan, T. E. Associations of Coffee, Tea, and Caffeine Intake With Risk of Breast, Endometrial and Ovarian Cancer Among Canadian Women. Cancer Epidemiology, 56: 75-82, 2018. Berretta, M., Micek, A., Lafranconi, A., Rossetti, S., DiFrancis, R., DePaoli, P., Rossi, P., and Facchini, G. Coffee Consumption Is Not Associated with Ovarian Cancer Risk: A Dose-Response Meta-Analysis of Prospective Cohort Studies. Oncotarget, April 17, 9(29), 20807-20815, 2018. International Agency for Research on Cancer (IARC, 2018). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Drinking Coffee, Mate, and Very Hot Beverages. Volume 116, World Health Organization, Lyon, France. http://publications.iarc.fr/566. See page 415. Torres-Collado, L, Garcia-d-la-Hera, M., Navarette-Munoz, E. M., Notario-Barandiaran, L., Gonzalez-Palacios, S., Zurriaga, O., Melchor, I., and Vioque, J. Coffee Consumption and Mortality From all Causes of Death, Cardiovascular Disease, and Cancer in an Elderly Spanish Population. European Journal of Nutrition. https//doi.org/10.1007/s00394-018-1796-9 Islam, M. T., Tabrez, S., Jabir, N. R., Ali, M., Kamal, M. A., Da Silva Araujo, L., De Loiveria Santos, J. V., Ferreira Da Mata, A. M. O., De Aguiar, P. S., and De Carvalho Melo Cavalcante, A. A. An Insight Into the Therapeutic Potential of Major Coffee Components. Current Drug Metabolism, 19: 544-556, 2018.

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In summary, I therefore conclude that there is no significant cancer risk resulting

from exposures to the listed carcinogens in coffee following the roasting, brewing, or drinking of coffee.

I remain, With Best Regards,

Joe Landolph Joseph R. Landolph, Jr., Ph. D. Associate Professor of Molecular Microbiology and Immunology and Pathology (With Tenure) Member, USC/Norris Comprehensive Cancer Center Keck School of Medicine

Associate Professor of Molecular Pharmacology and Toxicology (Secondary

Appointment) School of Pharmacy Member, Free Radical Institute Laboratory of Chemical Carcinogenesis and Molecular Oncology Norris Topping Tower, Room #4427A 1441 Eastlake Avenue USC/Norris Comprehensive Cancer Center Keck School of Medicine Health Sciences Campus University of Southern California

Los Angeles, California 90089-976. Member, Carcinogen Identification Committee Office of Environmental Health Hazard Assessment (OEHHA) 1001 I Street Sacramento, California 95812 jrl/JRL

From: Mack, ThomasTo: "Allan Hirsch (Allan.Hirsch@oehha.ca.gov)"Subject: coffeeDate: Monday, August 13, 2018 12:46:15 PM

Allan: A final set of comments on coffee. I wrote a note and followed up with a call to Lauren, andnow I will hit it again. I think it is important to address the problem publicly, but I have two majorbeefs with the document.

1. You have to explicitly explain why one wouldn’t expect the carcinogens in coffee to result inidentifiable cancers. They ARE still carcinogens, and while there may be interaction, that issheer speculation. The fundamental problem is simply dose. If you use a linear curve startingwith any of the observable carcinogenicity studies (animals per weight or humans) and run itback to the micro-doses in the coffee that addicts like me take, you would still produce acancer—but it would take a million person-years to see it. Please don’t mislead people intothinking that coffee magically turns eligibility for listing into ineligibility.

2. I don’t know what went through the IARC committee discussion, but the emphasis on“protection by coffee” is or is not true, but is completely irrelevant to the OEHHA mandate.They are necessarily completely separate processes. If it actually prevents, it does not do itby turning off a carcinogenic event, but by modifying the level of susceptibility to such anevent. Plenty of listed products are good for you, i.e. tamoxifen, but that does not alter thecarcinogenicity. Protection is a sideshow.

I think the agency looks foolish if the document continues to make both of these fundamentalerrors. And it doesn’t need to; the coffee lobby can still be win-win.Tom Mack

From: Dairkee, Shanaz, Ph.D.To: Vela, Monet@OEHHASubject: “CIC Peer Review, Listed Chemicals in Coffee”Date: Tuesday, August 14, 2018 2:22:19 PM

My comments on the proposed regulation are submitted below:

Upon reviewing the available scientific literature on the association between coffeeconsumption and cancer risk, I concur with the assessment of OEHHA scientists that anadverse role for coffee intake in cancer development and progression has not beenestablished to date. I am also in agreement that warning labels, such as those requiredunder Prop 65 to prevent inadvertent exposure to carcinogenic substances, arenot necessary for commercial coffee brewing and sales venues.

Shanaz H. Dairkee, Ph.D.Principal InvestigatorSenior Scientist, Cancer ResearchCalifornia Pacific Medical CenterResearch Institute475 Brannan StreetSan Francisco, CA 94107Phone: 415-600-1653

MEMORANDUM DATE: August 30, 2018 TO: Dr. Allan Hirsch, Chief Deputy Director

OEHHA FROM: Dr. Jason Bush CIC member Associate Professor Biology Department

California State University, Fresno SUBJECT: PEER REVIEW of PROPOSED NO SIGNIFICANT RISK LEVEL for LISTED CHEMICALS in COFFEE

I have read the ISOR information sent to committee members and reviewed the cited materials. The rationale for the proposed NO SIGNFICANT RISK for COFFEE seems logical and consistent with the considerable scientific evidence and the comprehensive review by IARC. I agree with the conclusion that exposures to listed chemicals in coffee pose NO SIGNIFICANT RISK. Feel free to contact me if further clarification is required (jbush@csufresno.edu; 559.278.2068).

J

AB