Document 0VX4DwbdL74wDapeDZDXBM3M

FILE NUMBER : 57 SEP 23i 1980 AUTHOR(S) s iCONOLLVt R. TITLE 5 ACUTE HEPATOTOXKIJ^E-VINYL CHLORIDE AND ETHYLENE; : MODIFICATION BY TRICHLOROPROPENE OXIDES DIETHYLMALEATE, s CYSTErNE. PUBLICATION SOURCE * TOXICOL APPL PHARMACOL 50r523-531,1979 LANGUAGE : ENG. , COUNTRY t USA AND ,, m-*-*-* eXPERI MENTAL DESIGN TRICHLOROPROPENE OXIDE (TCPO) IS AN IN VITRO INHIBITOR OF EPOXIDE HYDRABE AND AN IN VITRO DEPLETOR OF HEPATIC GLUTA THIONE. DIETHYLMALEATE (DEM) IB ALSO AN EFFECTIVE DEPLETOR OF HEPATIC GLUTATHIONE. CYSTEINE IS A RATE-LIMITING GLUTATHIONE PERCURSOR. MALE HOLTZMAN RATS (WEIGHING 170-150 e) WERE FED AD LIBITUM EXCEPT WHEN FASTED (18 HRS PRIOR TO VC OR ETHYLENE EXPO SURE) OR DURING EXPOSURE AND AFTER EXPOSURE. THE RATS WERE SACRIFICED: 24 HR AFTER THE START OF EXPOSURE (4 HR. EXPO SURE) FOR DETERMINATION OF SDH ACTIVITY} 2 OR 4 HR FROM THE START OF A 4 HR INHALATION EXPOSURE FOR GLUTATHIONE (NON PROTEIN SULFHYDRYL CONTENT) DETERMINATIONS. THE RATS WERE PRETREATED WITH ARCOLOR 1254 <PCB) ONCE/DAY FOR 3 DAYS. ON THE 3RD DAY VC OR ETHYLENE EXPOSURE BEGAN AFTER PRETREAT MENT. CYSTEINE <0.5 9/k9>* DEM (0.5 ml/k9> OR TCPO (0.1 ml/k9> WERE SAVAGED WITHIN 1/2 HR BEFORE THE START OF IN HALATION EXPOSURE. TO DETERMINE THE EFFECT OF TCPO ON THE HEPAT0T0X1 CITY OF yc: FARTED RATS JNHA gn HR EITHER 1000* 4500* OR B000 ppmiJFn RATS TNHALEQ 10000* 25000* OR 40000 PPm. THE EFFECT OF TCPO ON THE ACUTE HEPATOTOXICITY IN PCB-PRETREATED FASTED RATS WAS DETERMINED AFTER THEY INHALED EITHER 6000, 12000* 1B0B0, OR 15000 prim AND FED RATS INHALED EITHER 10000* 15000* OR 50000 PPf. FOR THE DETERMINATION OF THE EFFECT DEM HAS ON THE ACUTE HEPATOTOXICITY OF VC AND ETHYLENE* IN BOTH FED AND FASTED PCB PRETREATED* RATS . INHALED 10000 AND 10000 frit., RESPECT IVELY. THE EXPOSURES TO VC* IN PCB-PRETREATED FASTED RATS THAT WERE GAVAGED WITH CYSTEINE* WERE EITHER 5000* 0000* 12000* OR;17000 ppm. PCB-PRETREATED RATS GIVEN CYSTEINE WERE EXPOSED TO -EITHER 0000, 16000* OR 24000 rpri ETHYLENE. VEHICLE CONTROLS WERE RUN.WITH EACH GROUP. KEYWORDS VINYL CHLORIDE? ANIMAL STUDY? RATS? INHALATION? ACUTE HEPATOTOXICITY? ETHYLENE; TRICHLOROPROPENE OXIDE? DIETHYLMALEATE? CYSTEINE? POLYCHLORINATED BIPHENYL? GLUTATHIONE? EPOXIDE HYDRABEI MIXED FUNCTION OXIDASE SYSTEM; NONPROTEIN 8ULFMYDRYL CONTENT; SERUM SORBITOL DEHYDROGENASE? SDH? LIVER WEIGHT? FASTED RATS? AROCLOR 1254? ELECTROPHILE; METABOLISM? ARYL HYDROCARBON APOOOt1067 HYDROXYLASE. / ABSTRACTS -x-x- -M- -* AFTER INHALATION OF VC THE TCPO TREATED PCS (ARCOLOR 1254>-PRETREATED FASTED RATS SHOWED SIGNIFICANT ACUTE HEPATOTOXIC EFFECTS* I.E. , INCREASES IN LIVER WEIGHT AND SDH ACTIVITY. THE FASTED VEHICLE GROUP EXPOSED TO 4500 ppm HAD MINIMAL INJURY (SDH ACTIVITY 26.8)* BUT THE FASTED TCPO GROUP EXPOSED TO THE SAME CONCENTRATION HAD SIGNIFICANT EFFECTS <3DH ACTIVITY 133). HOWEVER* GLUTATHIONE <GSH> CONCENTRATIONS WERE NO DIFFERENT BETWEEN FASTED VEHICLE AND FASTED TCPO GROUPS. THE INCREASED TOXICITY OF VC IN TCPO PRETREATED RATS IS PROBABLY DUE TO INHIBITION OF EPOXIDE HYDRASE. THE IMPORTANCE OF EPOXIDE HYDRASE IS SHOWN WITH THE DEPLETION OF GSH IN BOTH GROUPS OF FASTED RATS. THE TCPO PRCTREATMENT IN FASTED RATS EXPOSED TO 25000 ppiti ETHYLENE SHOWED DEPLETED GLUTATHIONE AT 2 HR BUT NOT AT 4 HR* AND WAS FOUND NOT TO BE ASSOCIATED WITH THE HEPATOTOXIC RESPONSE TO ETHYLENE. THE DATA SUGGEST THAT EPOXIDE HYDRASE AND GLUTATHIONE-S-ALKYLEPOXYTRANSFERASE DO NOT. ACT ON ETHYLENE OXIDE. HOWEVER* ETHYLENE OXIDE MAY NOT BE A TOXIC METABOLITE OF ETHYLENE. FAST 1MS-.N0TL.DEM_TREATMENT SIGNIFICANTLY INCREASED--IHE. TOX ICITY .PEL 10000 ppm VC EXPOSURE IN PCB-PRETREATED RATS. THE Fed and fasTEITvehi cle^treated groups exposed f<5"T0000 ppm VC HAD DEPLETED GSH <N0 DIFFERENCE BETWEEN THE TWO GROUPS FOUND). IT APPEARS THAT SOME ACTION OF DEM IN ADDITION TO GLUTATHIONE DEPLETION* E.G. INHIBITION OF ARYL HYDROCARBON HYDROXYLASE <CYTOCHSOME P-488)* COULD EXPLAIN THE LACK OF POTENTIATION OF VC TOXICITY. THE DEM TREATED RATS EXPOSED TO 20000 ppia ETHYLENE HAD DE PLETED HEPATIC GSH IN BOTH FED AND FASTED RATS. HOWEVER* THE GSH DEPLETION IN THESE ETHYLENE EXPOSED RATS WAS NOT ASSOCIATED WITH ANY INCREASE IN TOXICITY (SDH ACTIVITY IN ALL ETHYLENE TREATED GROUPS WAS AROUND 300). CYSTEINE PREVENTED GSH DEPLETION AND THE ACUTE HEPATOTOXIC EFFECTS IN FASTED PCB PRETREATED RATS DURING EXPOSURE TO 8000 ppm VC. THE LIVER WEIGHT AND SDH ACTIVITY WERE SIG NIFICANTLY HIGHER IN VEHICLE TREATED THAN CYSTEINE TREATED. AN EXPOSURE TO 12000 ppm AND ABOVE OF VC. HOWEVER* CAUSED DEVELOPMENT OF HEPATOTOXIC EFFECTS. THEREFORE, CYSTEINE PROTECTION WAS NOT COMPLETE. THE DEVELOPMENT OF LIVER IN JURY IN THE CYSTEINE TREATED RATS EXPOSED AT THE HIGHER CONCENTRATIONS OF VC MAY BE DUE TO THE FACT THAT MUCH OF THE -SH WAS PRESENT AS CYSTEINE RATHER THAN GSH. CYSTEINE TREATMENT OF PCB-PRETREATED RATS HAD NO EFFECT ON THE TOXICITY OF ETHYLENE AT THE EXPOSURES TESTED. THERE FORE. GSH DOES NOT PLAY AN IMPORTANT ROLE IN ACUTE ETHYLENE HEPATOTOXICITY. THE AUTHORS CONCLUDE THAT IN PCB-TFfEATED RATS i LIVER GSH AND EH INFLUENCE THE ACUTE HEPATOTOXICITY OF VC. 4 fe i i * APOOO11068 SEP 23* 1990 FILE NUMBER * 226 y- AUTHOR(5) * TITLE t THE ZOCINNIICCAALL FFEEAATTUUBRDOERSOSOHFOWHEi PJA.THIC. ? AZNWGIEOLSLAINRGC*OMATA R! t FOUR CASES AND A REVIEW OF THE ENGLISH LITERATURE. PUBLICATION SOURCE MEDI ClNE < BALTIMORE) 58<1)84B-64.1979. LANGUAGE r ENG. \J L-* COUNTRY * USA na. b.a. ->*--**-**--**- EX PER X MENTAL DESIGN ****- THE REVIEW OF THE ENGLISH LITERATURE REVEALED 103 CASES OF HEPATIC ANGIOSARCOMA, WHICH 4 ARE DISCUSSED AS CASE RE PORTS. CASE 1? WAS A 42 YEAR OLD WHITE MALE* WHO HAD WORKED IN A VC POLYMERIZATION PLANT FOR 20 YRS. AND HAD A SIGNIFICANT ALCOHOL CONSUMPTION <A PINT OF WHISKEY/DAY). THE SECOND CASE* A 60 YR. OLD WHITE MALE* WAS ALSO EMPLOYED IN VC POLYMERIZATION ( FOR 37YRS.). CASE 3 WAS A 23 YR. OLD MALE WELDER WITH NO KNOWN EXPOSURE TO VC* THOROTRACT OR ARSENICALSi HOWEVER* HE HAD A LONG HISTORY OF ALCOHOL AND BARBITURATE ABUSE. THE FOURTH CASE IS A 63 YR. OLD WOMAN* WHO ALSO HAD NO KNOWN HISTORY OF EXPOSURE 70 ANGIOSARCOMA LINKED SUBSTANCES NOR ALCOHOL ABUSE. IN THE REVIEW ALL CASES OF iUiEttlLE-HEPATIC HEMANGIOENDOTHELIOMA (ANGIOSAR COMA) ARE EXCLUDED, KEYWORDS a* *-*.-** HUMAN; CASE REPORTS? HEPATIC ANGIOSARCOMA? VINYL CHLORIDE? PVC WORKERS; OCCUPATIONAL EXPOSURE? THOROTRAST? ARSENICALS? RADIUM? IDIOPATHIC HEMOCHROMATOSIS; NONEPIDEMIOLOGICAL CASES; MEDICAL HISTORY; ALCOHOL? ALKALINE PHOSPHATASE? TOTAL BILIRUBIN? HEPATIC ARTERIOGRAM? HYPERVASCULAR LESION? LAPAROTOMY? NODULAR LIVER? PORTAL FIBROSIS? CIRRHOSIS; LDH? SGOT? ADRIAMYCIN?CYCLOPHOSPHAMIDE? HEMORRHAGE? AUTOPSY? NEOPLASM? METASTASES?REGIONAL LYMPH NODES? LUNG? BONE? SKIN; LIVER SCAN? BIOPSY? HEPATOMEGALY? CARCINOEMBRYONIC ANTIGEN? CEA? ALPHAFETOPROTEIN? AFP? HEMIDIAPHRAGM? BILATERAL FILLING DEFECTS? HEPATOSPLENOMEGALY? ABDOMINAL PAIN? WEAKNESS? FATIGUE? WEIGHT LOSS? ASCITES? JAUNDICE; SPLENOMEGALY? THROMBOCYTOPENIA? PROTHROMBIN TIME? CLINICAL FEATURES? CHEMOTHERAPY; 3 FLOUROURrCIL? 5 FU. ***# ABSTRACTS *(* OF THE 103 DIAGNOSED HEPATIC ANGIOSARCOMA CASES 42X HAVE AN APPARENT ETIOLOGY? 22 PATIENTS WERE VC WORKERS* 15 PA TIENTS RECIEVED THOROTRAST* 2 PATIENTS WERE EXPOSED TO ARSENICALS* 1 PATIENT HAD BEEN EXPOSED TO RADIUM AND 3 HAD UNDERLYING IDIOPATHIC HEMOCHROMATOSIS. HEPATIC ANGIOSAR COMA OCCURS RARELY AND IS ABOUT 1/30TH AS COMMON AS HEPA TOCELLULAR CARCINOMA, ANGIOSARCOMA IS MORE COMMON IN MID DLE AGED MEN. OVERALL THERE IS A 4?1 RATIO* OF MALE TO FEMALE* AND IN THE NONEPIDEMIOLOGIC AND THOROTRAST SUB- AP00011069 IIB I8 H GROUPS THERE IS A 3d RATIO OF MALES TO FEMALES. THE MEAN AGE AT PRESENTATION OVERALL IS 53* HOWEVER* THE VC WORKERS HAVE A LOWER MEAN AGE. 50 AT THE TIME OF DIAGNOSIS. THESE DIFFERENCES AND OTHERS BETWEEN THE ETIOLOGICAL SUBGROUP IS PROBABLY DUE TO THE DIFFERENCES IN THE NATURE OF CARCINO GENIC EXPOSURE. THE INCREASE IN ANGIOSARCOMA CASES SINCE 1970 IS NOT ONLY DUE TO MORE SOPHISTICATED PATHOLOGICAL DIAGNOSIS* BUT AN INCREASED INCIDENCE. THE 15 THOROTRAST TREATED PATIENTS DEVELOPED ANGIOSARCOMA 24 YRS. AFTER INJECTION. THE 2 PATIENTS THAT TOOK ARSENICALS* FOWLER'S SOLUTION <IX ARSENIC) ORALLY* DEVELOPED ANGIOSARCOMA 24 YRS. AFTER THE FIRST INGESTION. THERE IS ONE CASE OF HEPATIC ANGIOSARCOMA CAUSED BY A RADIUM NEEDLE IMPLANT AND THE LATENCY PERIOD WAS ONLY 3 YRS. THE 3 PATIENTS THAT HAD IDIOPATHIC HEMOCHROMATOSIS (IRON DEPOSI TION THROUGHOUT THE BODY) DEVELOPED ANGIOSARCOMA AND ALL AT AUTOPSY REVEALED CIRRHOSIS. THE FINDINGS WITH THOROTRAST AND ARSENICALS INDICATE THAT MORE ANGIOSARCOMAS WILL BE DIAGNOSED IN THE FUTURE. THE ASSOCIATION WITH HEMOCHROMA TOSIS AND HEPATOMAS IS MUCH HIGHER THAN ANGIOSARCOMA INCI DENCE BUT THE AUTHOR BELIEVES IMPROVED TREATMENT WITH THE DISEASE WILL INCREASE THIS PERCENTAGE. IN THE.20.PATIENTS THAT WERE EXPOSED TO VC. THEY GENERALLY WERE HEALTHY UNTIL THE TIME OF TUMOR PRESENTATION. THE LATENCY PERIOD RANGED FROM 11 TO 37 YRS. (MEAN WAS 19 YRS.) AND IN HALF THE CASES EXPOSURES WERE CONTINUOUS* IN OTHERS INTERMITTENT. IN CASES 1 AND 2 THE PATIENTS WERE REFERRED* BECAUSE OF SOME ABNORMAL LIVER FUNCTION TESTS IN ROUTINE SURVEILLANCE SCREENING TESTS. CASE 1 WAS ASYMPTOMATIC* BUT CASE 2*S SYMPTOMS WERE WEIGHT LOSS* FATIGUE AND RIGHT UPPER QUADRANT PAIN AND HEPATOMEGALY WAS OBSERVED. THE SYMPTOMS OF HEPATIC ANGIOSARCOMA ARE NON-SPECIFIC AND CONSISTENT WITH MANY DIAGNOSES. THE MOST COMMON COMPLAINTS ARE ABDOMINAL PAIN* WEAKNESS* FATIGUE AND WEIGHT LOSS. MANY PATIENTS ARE SYMPTOMATIC AND A DIAGNOSIS IS GIVEN WHEN ROUTINE SCREENING OR TREATMENT FOR UNRELATED ILLNESSES RE QUIRES FURTHER INVESTIGATION. THE VC WORKERS TENDED TO HAVE LESS PROMINENT ABDOMINAL COMPLAINTS. OVERALL* THE HEPATIC ANGIOSARCOMA PATIENTS PRESENT SIGNS OF HEPATOMEG ALY. ASCITES AND JAUNDICE. BUT VC WORKES PESENTED THEM LESS COMMONLY AND SPLENOMEGALY WAS MORE PREVALANT. THE BIO CHEMICAL FINDINGS WERE ALSO NON-SPECIFIC* HOWEVER 62 HAD AT LAST ONE ABNORMAL TEST <64 TESTED/103 PATIENTS). THE MOST COMMON ABNORMALITY WAS ELEVATED ALKALINE PHOSPHATASE OR SGOT. THERE WERE COMMON HEMATOLOGICAL FEATURES SEEN* THROMBOCYTOPENIA (54%) AND ELEVATED PROTHROMBIN TIME (76%). THERE WERE NO CASES REPORTED WITH HEPATITIS ASSOCIATED ANTIGEN. CEA OR AFP. THE RADIOLOGICAL EVALUATIONS WERE NON-SPECIFIC TOO* EXCEPT FOR THE ARTERIOGAPHY (14/16 CASES). HEPATIC SCINTIGAPHY WAS ABNORMAL IN ALMOST ALL CASES TESTED (30/31). DISTINCT FILLING DEFECTS WERE FOUND IN 70X OF THE CASES. AND THE OTHERS HAD A NON-SPECIFIC NONHOMOGENE0US UPTAKE. THEREFORE* THE AUTHORS BELIEVE SCINTIGRAPHY MAY NOT BE A USEFUL SCREENING TEST FOR ANGIO SARCOMA. ARTERIOGRAPHY IS SUGGESTED AS A MORE USEFUL TOOL FOR DIAGNOSIS OF ANGIOSARCOMA AND THE EVALUATION OF RE SPONSE TO THERAPY. ANGIOSARCOMA WAS DIAGNOSED IN 65% OF r THE OPEN BIOPSIES COMPARED TO 257. OF THE CLOSED BIOPSIES. 167. OF ALL LIVER BIOPSIES LED TO BLEEDING, HEMMORHAGINGi AND LIGATION OF THE HEPATIC BLEEDING AND 3 PATIENTS DIED. ABDOMINAL BLEEDING WAS ALSO A PROBLEM ENCOUNTERED WITH THESE PATIENTS (277.). THE HEMORRHAGIC PROBLEMS SEEN MAY BE DUE TO PERIPHERAL DESTRUCTION OF BLOOD ELEMENTS? !..* IN TRAVASCULAR COAGULATION WITH THROMBOCYTOPENIA, HYPOPROTHROMBINEMIA, AND ELEVATED FIBRIN SPLIT PRODUCT (5V.M AND PERIPHERAL PLATELET DESTRUCTION (97.). CASE 2 HAD EVIDENCE OF PERIPHERAL PLATELET DESTRUCTION. ANTEMORTEM METASTASES WAS SEEN IN ONLY 7 PATIENTS (INCLUDING CASE 4>. THE PATIENTS GENERALLY LIVE FOR A SHORT PERIOD AFTER DIAGNOSIS, THE MEDIAN SURVIVAL WAS 5.5 MONTHS. THE MOST COMMON CLIN ICAL CAUSES OF DEATH ARE HEPATIC FAILURE AND INTRABDOMINAL HEMORRHAGE. CIRRHOSIS (20X) AND HEPATIC PORTAL FieoSIS (187.) WAS FOUND ON AUTOPSY. AUTOPSIES ALSO REVEALED META STASES, IN OVER 607. OF THE PATIENTS, INCLUDING LUNG, SPLEEN, ADRENAL, REGIONAL NODES AND BONE. NINETEEN OF THE 34 PATIENTS THAT WERE^DTASNOSD TO"ftAVE AN GIOSARCOMA AT BIOPSY WERE TREATED WITH CHEMOTHERAPY. THER APY WAS CURATIVE IN NO PATIENT, BUT SOME SHOWED"CLINICAL RESPONSES WITH IMPROVED STATUS ANDJEHPOT^ARY TUFlOR REGRES SION. THIS FINDING WAS REPORTED-^N THE 4 CASES DISCUSSED? THE INVESTIGATORS TREATED THE PATIENTS WITH ADRIAMYCIN, AND TWO PATIENTS HAD OBJECTIVE ANTITUMOR RESPONSES. TUMOR RE GRESSION HAS ALSO BEEN DESCRIBED IN PATIENTS TREATED WITH -CYCLOPHOSPHAMIDE OR 5-FLOUROURACIL (5-FU ) ALONE OR IN COMBINATION WITH SURGERY OR RADIOTHERAPY. \m APOOOt1071 SEP 23 19S0 FiLE NUMBER 300 AUTHOR<S> : :tot Rj fTITLE s :MTr^_ccccrTe QF rnor.MTr gypv : OF TOXIC SUBSTANCES PU&L I CAT I Oft--SOURCE--s--ENVI RON HEALTH PERSPECT 22: 155-159* 1978 LANGUAGE s ENG COUNTRY : GR BR . **-*--*--*- EXPERIMENTAL DES IGN -K- * 4JA THE AUTHOR PRESENTED A DOGMA AND STATISTICAL MODEL TO SUP PORT HIS OPINION. THE PROBABILITY OF GETTING A NEOPLASM OF INTEREST BY A GIVEN CHRONIC EXPOSURE IS GRAPHED P <a d>* WHERE A - THE AGE THAT CANCER INDUCTION IS FOUND AND D * AVERAGE DOSE RATE OF THE CARCINOGENIC AGENT IN UNITS PER DAY. IF IT IS ASSUMED THAT OTHER AGENTS MAY ALSO TRANSFORM THE CELL'S PHENOTYPE FROM NORMAL TO NEOPLASTIC* THE TOTAL EFFECTIVE DOSE CAUSING THIS CHANGE INCLUDES THE DOSE DUE TO BACKGROUND CARCINOGENS* SPONTANEOUS CELLULAR ACCIDENTS* *tc. PLUS THE DOSE OF THE CARCINOGEN OF INTEREST. THE AF FECT OF THRESHOLD WAS DISCUSSED* AS WELL AS COUNTER ARGU MENTS TO THE AUTHOR'S DOGMA. THREE MAIN TYPES OF DOSE- RESPONSE RELATIONSHIPS IN ANIMAL EXPERIMENTAL STUDIES* AND THE CONSEQUENTIAL STATISTICAL METHODS ARE PRESENTED. 193 , ' **** KEYWORDS ******* VINYL CHLORIDE! HUMAN POPULATION! RESIDENTIAL EXPOSURE! DOSE RESPONSE RELATIONSHIP! CARCINOGENS! THRESHOLD! RISK! probability; ambient air; statistical MODELS . **** ABSTRACT'S *** THE AUTHOR PRESENTS HIS DOGMA WITH A HYPOTHETICAL SITUA TION* WHERE_VC AMBIENT AIR LEVELS AROUND A UQ pi ant MJfiHT INDUCE CANCERS.AT THESE LOWER DOSE RATES <i..* SAY CANCERS ARE CAUSED AT 0.01 ppib AND THE AMBIENT CONCENTRA TION Tg flLBPl't mom'i THERE WILL BE FEWER CASES OF CANCERS THAN AT--HTGHER DOSE RATES. HOWEVER* THE AGE DISTRIBUTION WILL BE THE SAMEf THE CANCERS WILL BE PROPORTIONAL TO THE DOSE* AND NO THRESHOLD IS ANTICIPATED. USING THE STATISTICAL MODEL PRESENTED BY THE AUTHOR THE GRAPH OF P (a*d> AGAINST D HAS A POSITIVE SLOPE. THIS SUPPORTS THE AUTHOR'S DOGMA SINCE* AT LOW DOSE RATES: (i) THE AGE DISTRIBUTION OF EXTRA TUMORS IS INDEPENDENT OF THE DOSE RATE AND THAT EXPECTED NUMBER OF EXTRA TUMORS IS SIMPLY PROPORTIONAL TO THE DOSE. THE PATHOLOGICAL CHANGES IN MAN CAUSED BY CARCINOGENS MAY BE FOUND EVEN WITH AGENTS CONSIDEED TO HAVE THRESHOLD TYPE ACTION* SINCE MAN IS SO HETEROGENEOUS. THEREFORE* THE AUTHOR BELIEVES HIS DOGMA SHOULD BE THE FOUNDATION OF REGULATORY ACTION. APOOO11072 there are two counter arguments presented* <i> the level WHEN A THRESHOLD IS OBSERVED AND <2> THAT AT LOW ENOUGH DOSE LEVELS ALMOST ALL TUMORS WOULD OCCUR LONG AFTER AGE 100 AND SO WOULD BE IRRELEVANT TO THE HUMAN CONDITION. THE AUTHOR INDICATES THE FIRST COUNTER ARGUMENT DOES NOT TAKE INTO CONSIDERATION BACKGROUND CARCINOGENS AND DEPENDS ON A SAFE RISK RATHER THAN A ZERO RISK. THE SECOND COUNTER ARGUMENT IS BASED ON STUDIES WHERE HIGH LEVELS OF CARCINO GENIC AGENTS WERE GIVEN REPEATEDLY TO EXPERIMENTAL ANIMALS. THIS COUNTER ARGUMENT IS CONSIDERED BY THE AUTHOR TO BE BASED ON TOO HIGH DOSE LEVELS GIVEN TO EXPERIMENTAL ANIMALS AND ONLY THE FIRST OF SEVERAL TUMORS THAT THE ANIMAL DE VELOPS WOULD BE OBSERVED. THE EX PEIMENTALLY OBSERVABLE RANGE AT WHICH ATTRIBUTABLE RISK CAN BE CHARACTERIZED IS 10% AND UPWARDS. MATHMATICAL MODELS ATTEMPT TO USE THESE EXPERIMENTAL RESULTS TO ESTI MATE THE DOSE RESPONSE DATA TO ESTIMATE THE DOSE RESPONSE RELATIONSHIP IN THE UNOBSERVABLE RANGE (1% AND DOWNWARDS) WHICH MAY BE VALID AS A BASIS FOR LEGISLATION. THE AUTHOR PRESENTS 3 CASE GRAPHS SHOWING: (1) DOSE LINEAR GRAPH THROUGH ZERO WITH THE UPPER AND LOWER CONFIDENCE LIMITS ON THE RISK AT LOW DOSES. WHICH GENERALLY DIFFER FROM EACH OTHER BY LESS THAN A FACTOR A 2? <2> NO SIGNIFICANT EFFECT AT ANY OF THE DOSE LEVELS WITH A LOWER CONFIDENCE LIMIT OF ZERO AND THE UPPER CONFIDENCE LIMIT A STRAIGHT LINE THROUGH 2ERO. THEREFORE THIS SUBSTANCE SHOWS NO CARCINOGENICITY: <3> AN UPWARD CURVATURE OF THE DOSE RESPONSE IN THE OBSER VABLE RANGE TO SUGGEST EITHER THAT A THRESHOLD EXISTS OR THAT THE RISK AT THE LOWEST DOSE MAY B MUCH LESS THAN 0.1 OR 0.01 TIMES THE EFFECT AT THAT DOSE LEVEL. CASES 1 AND 3 ARE CONSIDERED SUFFICIENTLY ACCURATE TO ASSIST IN RATIONAL LEGISLATION. APOOOIf 073