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ISTOCONSULT DEL DN. ANGELO CEAIOLt LASORAT. E UFF.: VIA GRIITI, 12 • TEL. (0374) SW2 0 ASITAZIONE : VIA FULCNERIA, 29 - TEL (0374) 5760 2dp12 CASTELLEONE (CR) ITW..Y Cod. Fisc. CRL NGL 35R03 D150r Partita LVA. 00714720190 Recapiti: T.La 310470 Provib. T.Lf.x (0371) 57880 Caatelieone AUGUST IdTH. 19% TO THE PROJECT OFFICER FOR ENVIR.TOB.SMOKE TECHNICAL INFORMATION STAFF _ OFFICE OF HEALTH AND ENVIRON.ASSESS. (RD-0) U.S. ENVIRONMENTAL PROTECTION AGENCY wASH I NGTON D. C. 20460 U,S.A. REF.: EPA DRAFT ON ENVIRONMENTAL TOBACCO SMOKE , E,T,S. SIRS, APPENDIX D INVESTIGATES ALTERNATIVE METHODS BASED ON DOSE/RESPONSE MODELLING TECHNIQUES AS AN ALTERNATIVE APPROACH FOR ESTIMATING THE YEARLY NUMBER OF LUNG CANCER DEATHS IN NON SMOKERS DUE TO E,T.S. THREE PROPOSED GENERAL APPROACHES ARE PRESENTED IN THIS DOCUMENT FOR DERIVING E.T,S. DOSE/RESPONSE MODELS AND THE PURPOSE OF PRESENTING THESE PRELIMINARY APPROACHES IS TO INVITE COMMENTS ON THEYR RELATIVE MERIT AND SOLICIT ADVICE. I HAVE DECIDED TO WRITE AND I WILL EXPRESS HERE WHAT I THINK ABOUT APPROACH 1 ( RELATIVE POTENCY APPROACH ) WHICH IS BASED ON THE ESTA- BLISHEMENT OF A DOSE EQUIVALENT RELATIONSHIP BETWEEN E,T.S, AND A POSITIVE CONTROL AS INHALED BENZO(A)PYRENE - B(A)P. QUITE FRANKLY : THE IMPRESSION I HAVE RECEIVED AFTER HAVING EXAMINED THIS PART OF THE DOCUMENT AND HAVING ALSO EXAMINED THE REFERENCE LITERATURE IS THAT, THE SUBJECT OF THIS PAPER BEING E.T.S, ONE FEELS FREE OF SAYING WHAT ONE WANTS, THIS FEELING IS ALSO ENFORCED BY READING THIS PARAGRAPH ON PAG,1 OF THE INTRODUCTION WHERE THIS RATHER DOGMATIC STATEMENT IS GIVEN : " THE ENVIRONMENTAL PROTECTION AGENCY (EPA) PRESUMES THAT.THERE IS NO SUCH THING AS RISK-FREE EXPOSURE TO A CARCINOGEN. UNLESS THERE IS EVIDEN- CE OF THE CONTRARY, EPA BELIEVES THAT ANY EXPOSURE TO A CANCER CAUSING AGENT-REGARDLESS OF LEVEL-INCREASES THE RISK OF CANCER. THE FACT THAT ACTI- VE SMOKING CAUSES LUNG CANCER. THEREFORE. SUGGESTS THAT NONSM()E(ERS EXPO- SED TO E,T.S. ARE ALSO AT RISK FOR LUNG CANCER, ALTHOUGH AT A MUCH LOWER LEVEL THAN SMOKERS.I' ( * ) M CONCERNING THIS POINT SEE MY COMMENT AT PAGE.4 PAR.2-B) V .is w .cs .w1

ISTOCONSULT DEL DR. ANGELO CERIOU PAGE 2 IN FACTS THE EXERCISE THAT E.P.A. PROPOSES: CONVERT E.T.S. TO A STANDARD AGENT B(A)P THAT HAS A KNOWN INHALATION DOSEAESPONSE MODEL ASSOCIATED WITH IT, INVOLVES A SEQUENCE OF EXTRAPOLATIONS AND OVERSEMPLIFICATIONS (ONE WOULD BE ATTEMPTED TO SAY A SALADE OF EXTRAPOLATIONS AND OVERSEMPLIFICATIONS ) BETWEEN EXPERIMENTS DONE IN VA' RIOUS ANIMAL SPECIES, WITH DIFFERENT CHEMICALS, AT DIFFERENT TIMES AND USING TOTALLY NON-COMPARABLE WAYS OF ADMINISTRATION, THE MAIN PURPOSE OF ALL THIS , SEEMS TO ME, BEING TO FIND, NO MATTER HOW, SOME SUPPORT TO THE DOGMA EXPRESSED ABOVE. I WANT TO STRESS IN DETAIL THE MAIN POINTS ON WHICH I DISAGREE WITH EPA : A) ESTIMATING E.T.S. RELATIVE POTENCY TO OBTAIN AN E,T,S. DOSE/RESPONSE MODEL .(IN TERMS OF HUMAN LUNG TUMOUR RESPONSE !!) EPA PROPOSES TO ESTABLISH THE REALTIVE CARCINOGENIC POTENCY OF E,T,S. COMPARED TO AN APPROPRIATE'STANDARD : THE CHOICE OF THIS STANDARD HAS BEEN B(A)P; CANDIDATE STUDY TO ARRIVE TO THIS TARGET IS THE WORK OF GRIMMER ET AL. (190. THE CHOICE OF THIS WORK CLEARLY INDICATES THAT NOTHING ELSE WAS AT HAND, IN FACTS : 1-A) IN THIS STUDY THE RATS WERE TREATED ONCE VIA INTRAPULMONARY IN- JECTIONS OF BEE-WAX TRIOCTANOIN PELLETS THAT WERE THE CARRIER VEHICLES OF VARIOUS FRACTIONS OBTAINED BY E.T.S. THIS, I THINK, IS NOT AN ADVANTAGE AT AI_L OF THIS METHOD FOR COMPARI- SON PURPOSES BUT A SERIOUS BIAS. 2-A) THE ENTIRE E.T.$. CONDENSATE WAS NOT EVALUATED, THIS SEEMS ALMOST INCREDIBLE SINCE THE WORK SHOULD HELP ESTIMATING THE RELATIVE POTENCY OF E,TS. THE PRETENTION THAT DOSE ADDITIVITY OF THE E.T,S. FRACTIONS MUST BE ASSUMED TO OBTAIN THE RELATIVE POTENCY OF E.T.S. OF THE ENTIRE SAMPLE CANNOT BE SUPPORTED IN TOXICOLOGY. 3-A) THE FACT THAT TUMOURS WERE EPIDERMOID CARCINOMAS AT THE IMPLANTA' TION SITE DOES NO GO AT ALL AGAINS THE EVIDENCE OF HUMAN PATHOLOGY. 4-A) THE MOST IMPORTANT POINT OF THE WORK OF GRIMMER HAS. IN MY OPINION , BEEN OMITTED : ONLY 0.17 Z OF TEH SIDESTREAM SMOKE POLINU' CLEAR HYDROCARDBONS CARCINOGENIC EFFECT CAN BE ATTRIBUTED TO THE B(A)P

ISTOCONSULT DEL DR. ANGELO tMW PAGE 3 PRESENT, A RESPONSE OF THIS AMPLITUDE DOES NOT JUSTIFY IN MY OPINION. THE CHOICE OF B(A)P AS A STANDARD. ON THIS MATTER ALSO SEE POINT 1-B-1 BELOW. ALSO TOTALLY NEGLECTED HAVE BEEN THE CONCLUSIONS OF THE N.R.C. REPORT 19% ON THE SAME SUBJECT, CONCLUSIONS I WILL QUOTE HERE :.. MEASUREMENTS OF B(A)P LEVELS IN E.T,S. INAPPROPRmATELY REFLECT TOTAL ENVIRONMENTAL B(A)P WHICH INCLUDES CONTRIBUTIONS FROM COOKING, COAL BURNING AND OTHER SOURCES., THE LARGE UNCERTAINITY IN Do SEEN IN TAB. D 4 RESTRICTS THE UTILITY OF THESE DOSIMETRIC CALCULATIONS , ESPECIALLY GIVEN THE LACK OF KNOWLEDGE CONCERNING THE IDENTITY OF THE ACTIVE CARCINOGENS IN E.T.S. AND MAINSTREAM SMOKE. B) THE SECOND STEP PROPOSED ONCE THE RELATIVE POTENCY OF E,T,S TO THE STANDARD AGENT B(A)P HAS BEEN ESTIMATED IS THAT EPA WOULD USE THIS RESULT TO DETERMINE THE STANDARD EQUIVALENT EXPOSURE UNITS WHICH AP.E SURSTITUTED INTO THE STANDARD INHALATION DOSE/RESPONSE MODEL TO OBTAIN A CANCER RISK ESTIMATE. THREE ARE THE POTENTIAL CHOICES PROSPECTED : 1-B) HAMSTER INHALATION B(A)P DOSE RESPONSE ACCORDING TO THE ELEMENTS OBTAINED BY THYSSEN ET AL.(1981); THIS WORK IS QUOTED AS"THE ONLY PURE PAH INHALATION EXPERIMENT PRESENTLY AVAILABLE THAT CONTAINS SUFFICIENT INFORMATIONS TO ESTABLISH A DOSE/RESPONSE RELATIONSHIP". MY MAIN POINTS OF CRITICISM ARE : 1-B - 1) THERE IS NO LUNG TUMOUR INDUCED IN THIS EXPERIMENT 1-B - 2) I DISAGREE THAT THIS COULD BE REGARDED AS A "PURE PAH EXPERIMENT" SINCE B(A)P WAS NOT INHALED PURE AT ALL BUT WITHIN AN NACL AEROSOL AND ONE IGNORES WHICH THE ADDITIVE EFFECT OF NACL HAS BEEN NOT SO MUCH IN TERMS OF BIOAVAILABILITY BUT IN TERMS OF TOPICAL EFFECTS ON THE UPPER RESPIRATORY TRACT 1-B - 3) 1 CANNOT UNDERSTAND ON WHICH BASIS EPA CAN SAY "WHEN CONFRONTED WITH INHALATION EXPOSURES OF COMPLEX PAH MIXTURES THE APPROACH USED BY EPA {M USUALLY BEEN TO ASSUME THAT THE ENTIRE PAH MIXTURE IS AS POTENT As R(A)P,,, aV WHICH BASIS IS IT POSSIBLE TO SAY THIS CONSIDERING WHAT HAS BEEN STATED ABOVE AT POINT 1-B - 1 ? EPA ASSUNPTION IS ALSO CONTRADICTED BY THE RESULTS OF GRINMER ET AL (19$)

ISTOCONSULT DEL DR ANGEIO CERIOU PAGE 4 MAY I SUGGEST YOU READ MORE CAREFULLY THE PARAGRAPH RESULTS AND DiSCUSSION AT PAGE 176 OF THIS ARTICLE ? 2-B) RAT INHALATION DIESEL ENGINE EXAUST I)USE/RESPONSE, THE WORK OF MAUDERLY ET AL.(I987) I S QUOTED BUT TH I S WORK I S NOT i_ I STED IN THE BIBLIOGRAPHICAL REFERENCES AND IT HAS NOT BEEN POSSIBLE TO SEE IT. THE AUTHORS OF THIS WORK ARE SAID TO HAVE OBTAINED A DOSE/RESPONSE MODEL FROM TNEYR EXPERIMENTAL RESULTS BUT "THEYR DERIVED MODEL WOULD NOT BE CONSISTENT WITH THE REGULATORY ASSUMPTIONS OF LOW DOSE LINEARITY", THIS MAKES ME THINK THAT THE AUTHORS DID NOT OBTAIN DOSE/RESPONSE RESULTS AT ALL. IF I UNDERSTAND CORRECTLY EPA POINT OF VIEW A LINEAR REALTIONSHIP BETWEEN EXPOSURE AND DOSE IS CONSTANTLY ASSUMED IN EXTRAPOLATING RESULTS OBTAINED FROM BOTH EPIDEMIOIAGICAL DATA AND ANIMAL DATA RESULTING FROM HIGH LEVEL OF O(POSIA2E, I THINK IT IS IMPORTANT TO RECOGNIZE THAT THIS MAY BE AN ERRO- NEOUS ASSUMPTION. IT IS CONCEIVABLE THAT AT HIGH LEVEL OF EXPOSURE AS COM- PARED TO LOW LEVELS, THE DOSE TO CRITICAL BIOLOGICAL TISSUES MAY BE EITHER HYPERLINEAR OR HYPOLINEAR, DEPENDENT UPON THE SPECIFIC MECHANISMS INVOL- VED IN THE DEPOSITION, CLEARANCE AND METABOLISM OF THE MATERIAL. OF a)URSE THERE IS MUCH MORE TO SAY ON THIS TOPIC BUT THIS WOULD BE BEYOND THE SCOPE OF THIS LETTER, 3-B) HUMAN INHALATION COKE OVEN I)OSE/RESPONSE UP TO NOW I HAVE BEEN UNABI_E TO OBTAIN THE PERTINENT i_ITERATURE; ONE OF THE WORKS QUOTED, A1_BERT ET AL,(I%2) CANNOT BE FOUND FOLLOWING THE INDICATIONS REPORTED IN THE BIBLIOGRAPHY (MISQUOTING? VOLUME IS NOT IN- DICATED). I WILL EVENTUALLY CONMENT LATER , ONCE THE QUOTED LITERATURE WILL BE AVAILABLE TO ME. I NOTE ANYWAY THIS SENTENCE ON PAGE D 13 : "TWO DIFFERENT BIOASSAYS SYSTEMS ARE REQUIRED TO OBTAIN COKE OVEN EQUIVALENT EXPOSURE UNITS FOR E,T,S. (I.E. E.T.S. COMPARED TO B(A)P LUNG IMPLANT AND COKE OVEN EMISSIONS COMPARED TO B(A)P SKIN PAINTING IN OTHER WORDS : FROM HUMAN EPIDEMIO1_OGICAL DATA FROM COKE OVEN WORKERS TO HAMSTER AND MICE AND BACK AGAIN TO MAN EXPOSED TO E,T.S. AM I CORRECT ? THIS IS NOT SIMPLY A DISADVANTAGE , IN MY OPINION THIS CANNOT BE DDNE,

ISTOCONSULT DEL DII. ANGELO CERIOU PAGE 5 MY FINAL POINT COMES FROM PAGE D 1. EPA SAYS IT HAS SUFFICIENT INFORMATION ABOUT THE TIME WEIGHTED EXPOSURE TO E.T.S, IN THE NON SMOKING POPULATION, How CAN THAT POSSIBLY BE SINCE NO ONE ELSE HAS THAT? IN APPENDIX C EPA ASSUMES EXPOSURE CONDITIONS AND INTAKES (SEE PAG.C'17). IF ASSUMPTIONS LIE AT THE BASE OF EPA DOSIMETRIC DISCUSSIONS HOW CAN EPA STATE IN APPENDIX D THAT IT HAS SUFFICIENT INFORMATION ON TIME WEIGHTED E.T.S. EXPOSURE TO CONSIDER ANY OF THE MODELS (NOT JUST THE RELATIVE POTENCY APPROACH) DISCUSSED IN APPENDIX D.? CONCLUSIVE REMARKS MY FEELING IS THAT EPA WOULD NOT ACCEPT, CORRECTLY. ARGUMENTS FROM THE INDUSTRY WHICH ARE OF THE QUALITY OF THOSE USED IN APPENDIX D TO SUPPORT THE "RELATIVE POTENCY APPROACH" BECAUSE THEY ARE DEVOID OF PRACTICAL AND SCIENTIFIC VALUE. OF COURSE THE SAME PRINCIPLE MUST BE VALID FOR EPA ITSELF, THIS PART SEEMS TO HAVE BEEN WRITTEN WITH LITTLE CARE SO THAT REFERENCES ARE GIVE THAT ARE NOT REPORTED AT ALL IN THE BIBLIOGRAPHY , MAUDERLY ET AL UgH7) , OR ARE INDICATED IN AN IMPRECISE WAY AND CANNOT BE FOUND AS W_BERT ET AL. (1982), THE CONCLUSION I HAVE DRAWN HAVING EXAMINED THIS PART OF THE EPA DOCUrENT IS THAT FROM THE BIOI.OGICAL-EXPERIMENTAL POINT OF VIEW THERE IS NO EVIDENCE PROVING THAT E.T.S. HAS A CARCINOGENIC EFFECT AND THEREFORE THE IMPACT OF AN EXERCISE AS THE RELATVE POTENCY APPROACH FOR DERIVING E.T.S. DOSE/RESPONSE MODELS TO PREDICT CONDITIONS OF HUMAN EXPOSURE COULD ONLY BE MISLEADING OR, IN THE BEST HYPOTHESIS USELESS ,- FAITHFULLY YOURS - - 0) CI1t A. DR,ANGELO CERIOLI w sch OD