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Arsenic Risk AssessmentHeather Carlson-Lynch, Barbara D. Beck,2 and Pamela D. Boardman21ChemRisk Division, McLaren/Hart Environmental Engineering Corporation, Portland,ME 04102 USA; 2Gradient Corporation, Cambridge, MA 02138 USA

In this commentary, we respond to theconclusions of recent publications byHopenhayn-Rich et al. (1) and Smith et al.(2) regarding issues of arsenic risk assess-ment. Although Hopenhayn-Rich et al.was not published in Environmental HealthPerspectives, we believe that it is importantto examine these studies and their rele-vance to risk assessment together.

In 1988 the Risk Assessment Forum ofthe U.S. Environmental Protection Agencydeveloped a cancer slope factor (CSF; theU.S. EPA estimate of carcinogenic poten-cy) for arsenic based on an ecological epi-demiology study relating skin cancer toarsenic ingestion in Taiwan. Several impor-tant questions have been raised about thisCSF. One issue with this CSF is that itassumes a linear dose-response relationshipfor cancer, and thus it does not reflectincreasing evidence indicating either athreshold or a sublinear dose-responserelationship for low doses of arsenic (3,4).[Saturation of the methylation detoxifica-tion pathway has been proposed as oneexplanation for the sublinear dose-response relationship for arsenic (5).]Another issue is whether ingestion ofarsenic is associated with cancers otherthan skin cancer.

EPA is currently under a judicial man-date to evaluate whether the existing maxi-mum contaiminant level (MCL) should berevised (the current MCL is 50 pg/l). Inevaluating the existing MCL and the possi-ble need for a revised MCL, EPA will likelyconsider recent publications regarding theissues of the methylation threshold andinternal cancers. Two recent publications[Hopenhayn-Rich et al. (1) and Smith etal. (2)] are seemingly pertinent to theseissues; however, as described below, wefound that these publications have defi-ciencies that limit their applicability tothese regulatory questions. The studiesused by Hopenhayn-Rich et al. were notdesigned appropriately to address themethylation threshold issue. The paper bySmith et al. failed to address a variety ofsignificant uncertainties that call into ques-tion their risk assessment model.

Hopenhayn-Rich et al.Methylation is generally accepted as ametabolic detoxification mechanism forlow doses of inorganic arsenic (5).Hopenhayn-Rich et al., however, questionthe conclusion of the EPA ScienceAdvisory Board that "at dose levels below200 to 250 pg As3/person/day [where

metabolic saturation begins] there is a pos-sible detoxification mechanism (methyla-tion) that may substantially reduce cancerrisk from the levels EPA has calculated"(5). Using data from previously publishedstudies, Hopenhayn-Rich et al. used per-cent inorganic arsenic in urine as a measureof non-detoxified arsenic and total urinaryarsenic concentration as a measure ofarsenic dose and applied simple linearregression to determine whether the per-centage of inorganic arsenic increases withincreasing dose. Their results failed toshow a correlation between percent inor-ganic arsenic and urinary arsenic concen-tration and, on that basis, the authors con-cluded that there is no consistent evidenceto support the methylation thresholdhypothesis in humans.

The Hopenhayn-Rich et al. evaluationdoes not, however, demonstrate the ab-sence of a methylation threshold for thefollowing reasons:

- The average arsenic exposures inalmost all of the studies analyzed were toolow to observe methylation saturation.Evidence from the study by Buchet et al.(6) suggests that methylation would becompletely saturated at exposures greaterthan 500 pg/day, with corresponding totalurinary arsenic output of approximately290 pg/day at steady state. If average dailyurine output is 1.5 1/day (1), this is equiva-lent to an average urinary arsenic concen-tration of about 190 pg/l. Among the 28populations analyzed by Hopenhayn-Rich,only two populations (7,8) had average uri-nary arsenic concentrations at or above 190pg/l (238 and 245 pg/I, respectively); aregression analysis on the individual datawithin the Yamauchi et al. (7) populationwas borderline significant at p = 0.10 [indi-vidual data were not available for theFarmer and Johnson population (8)].

* The authors used urinary arsenic con-centrations from grab samples as the basisfor evaluating methylating capacity.However, the proportion of inorganicarsenic excreted in the urine varies substan-tially over time; thus, an individual grabsample is not representative of the degreeof methylation that is occurring. Studies byBuchet et al. (6) show that after ingestionof inorganic arsenic, the proportion ofarsenic in the urine that is inorganicarsenic is high soon after exposure (0-12hr), but much lower later on (>12 hr).The appropriate measurement with whichto examine metabolism and elimination ofarsenic is the total mass of inorganic

arsenic and its metabolites eliminated overa 24- to 48-hr time period; using mass pertime rather than concentration wouldcontrol not only for variability in the pro-portions of the metabolites over thecourse of a day, but also for variability inurine volume. A recent 7-day diet study inJapan found that the intake and excretionof total arsenic were balanced when aver-aged over a week but not over 1 day (9).

Smith et al.Currently, the CSF for ingested arsenic isbased on the incidence of nonmelanomaskin cancers associated with exposure tohigh levels of arsenic in drinking water inTaiwan; however, Smith et al. have sug-gested that arsenic could be an importantrisk factor not only for skin cancer, butalso for several internal cancers includinglung, liver, bladder, and kidney. Smith etal. used the data from another epidemio-logical study in Taiwan (10) to examine

Address correspondence to B.D. Beck, GradientCorporation, 44 Brattle Street, Cambridge, MA02138 USA.Received 5 October 1993; accepted 9 February1994.

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whether there might be an associationbetween ingested arsenic and internal can-cers [these data are described in greaterdetail in a more recent epidemiologicalstudy in Taiwan (11)]. The authorsapplied simple linear regression to datafrom the Taiwanese study and found a lin-ear relationship between well water con-centrations of arsenic and mortality ratesfor liver, lung, kidney, and bladder cancer.The U.S. lifetime risk of cancer due toconsuming 1 I/day of drinking water con-taining 50 pg/I arsenic was estimated bySmith et al. to be 13/1000 (2: Table 5).This risk may be converted to a CSF of 18(mg/kg-day)'l for administered dose,which is approximately 10 fold higher thanthe current CSF of 1.75 (mg/kg-day)'.

-We noted the following deficiencies inthe analysis of Smith et al., particularly inrelation to risks in U.S. populations:

* In deriving risk estimates associatedwith arsenic exposure using linear regres-sion, Smith et al. assumed that the arsenicintake of the control population was zero.This assumption is unrealistic given othersources of arsenic in the diet and wouldinflate the CSF by artificially increasing theslope of the exposure-response curve.

* Smith et al. did not discuss the impli-cations of detoxification in estimatingpotential risks from low-level exposurestypical of the U.S. population (an estimateof typical U.S. background exposure isabout 22 pg/day). The estimated exposurelevel of 22 pg/day As for the U.S. popula-tion is substantially lower than an estimat-ed 2130 pg/day As for the Taiwan studypopulation [based on a concentration of0.47 mg/l As in drinking water (12,13)and assuming a water consumption rate of4.5 I/day and 18 pg/day As in food, usingthe most current EPA arsenic intake esti-mates for Taiwan (14)]. As noted above,the EPA Science Advisory Board recom-mends that arsenic detoxification be con-sidered in the risk assessment of exposuresbelow 200-250 pg/day (5). This recom-mendation represents a level below whichmethylation is not compromised.According to Buchet et al. (6), saturationof methylation begins at this level and iscomplete at levels greater than 500 pg/day.

* Smith et al. did not consider keyuncertainties in the use of the Taiwan datain their analysis. For example, blackfootdisease and bladder cancers are associatedwith fluorescent humic acids found in theTaiwanese drinking water (15,16). Thepotential role of humic acids in bladdercancer etiology (or other cancer types)makes conclusions regarding any quantita-tive association between arsenic and canceruncertain. In addition, it may render theextrapolation from Taiwanese expos-ure-response data to risks from arsenic in

drinking water in the U.S. questionable.This may be an important considerationnot only for evaluating the paper of Smithet al., but possibly for evaluating the validi-ty of the present CSF.

* Smith et al. did not address (nor doesthe current CSF) the differences betweenthe Taiwanese and U.S. populations thatwould reduce the accuracy of using expo-sure-response data from Taiwan for U.S.populations. For example, the average pro-tein intake (which would influence theextent of detoxification of arsenic) in theblackfoot disease endemic area was only65% of the current average U.S. proteinintake, potentially compromising thedetoxification of arsenic and invalidatingthe CSF for use in U.S. populations.Average protein intake in the blackfoot dis-ease endemic area in 1975 was 44.1 g/dayin women and 65.3 g/day in men (17;Guo H-R, personal communication); aver-age U.S. protein intake is 65-70 g/day inwomen and 90-110 g/day in men (18).Additionally, the intake of methionine (anamino acid necessary for arsenic methyla-tion) (10) plus cystine was very low in theendemic area [1.2 g/day (15)] compared tothe average U.S. intake [2.3-2.5 g/day inwomen and 3.2-3.9 g/day in men (16)]. Infact, the intake of methionine alone wasdeficient; the average intake was 70% ofthe recommended daily minimum (17;Guo H-R, personal communication).

The exposure parameters for theTaiwan study that were used by Smith etal. may have biased the cancer risk esti-mate. EPA recently approved a referencedose (RfD) for arsenic (using the Tai-wanese data) that uses a water consump-tion rate for males and females combinedof 4.5 1/day (14), as compared to the valuesof 3.5 and 2 1/day for males and females,respectively, used by Smith et al. In addi-tion, the RfD derivation assumed a back-ground dietary arsenic intake of 2 pg/day(18), based on estimates from Taiwan of30 pg As/kg in rice and a daily rice con-sumption of 0.225 kg, and the assumption(from an FDA survey) that 35% of arsenicin rice was inorganic. In contrast, Smith etal. assumed that the background intake inTaiwan was zero. Consequently, CSFs cal-culated using the revised EPA exposureparameters would be significantly lowerthan those calculated by Smith et al. [Wealso note that use of the revised exposureparameters would also decrease EPA's pre-sent CSF for skin cancer (19)].

In summary, the Smith et al. andHopenhayn-Rich et al. analyses are flawed.Hopenhayn-Rich et al. do not provide abasis for dismissing the methylationthreshold hypothesis as the basis for theapparent lack of carcinogenicity of arsenicat low levels. We recommend that arsenic

regulation should not consider anydose-response relationship between arsenicand internal cancers based on the Smith etal. analysis because of the deficiencies dis-cussed above. Mechanistic or more refinedepidemiological studies are needed to assessthe possible relationship between internalcancers and arsenic ingestion. An exampleof such a study is provided by a recent epi-demiological study conducted in Taiwanwhich found no consistent associationbetween the arsenic level in well water andurinary cancer incidence with arsenic levelsless than 0.32 ppm and a statistically sig-nificant association between arsenic andbladder cancer at levels greater than 0.64ppm, thus indicating a possible nonlineardose-response relationship between arsenicexposure and urinary cancer (20). In addi-tion, a similar association was also observedfor transitional cell renal cancer, but notrenal cell renal cancer. It should be notedthat this study involved approximately 11million individuals residing in 243 town-ships and used 10 exposure groups. Thiscontrasts with the study used by EPA toderive the current CSF, which involvedapproximately 40,000 individuals in 37villages, using only 3 exposure groups(12,13). Furthermore, we recommend thatfuture risk assessments for arsenic considerevidence for a sublinear arsenic-inducedcancer dose-response relationship, as rec-ognized by the EPA's Science AdvisoryBoard (J0).

REFERENCES

1. Hopenhayn-Rich C, Smith AH, Goeden HM.Human studies do not support the methylationthreshold hypothesis for the toxicity of inor-ganic arsenic. Environ Res 60:161-177(1993).

2. Smith AH, Hopenhayn-Rich C, Bates MN,Goeden HM, Hertz-Picciotto I, Duggan HM,Wood R, Kosnett MJ, Smith MT. Cancer risksfrom arsenic in drinking water. Environ HealthPerspect 97:259-267(1992).

3. Petito CT, Beck BD. Evaluation of evidence ofnonlinearities in the dose-response curve forarsenic carcinogenesis. Trace Sub EnvironHealth 24:143-176(1990).

4. Marcus WL, Rispin AS. Threshold carcino-genicity using arsenic as an example. In: Riskassessment and risk management of industrialand environmental chemicals (Cothern CR,Mehlman MA, Marcus WL, eds). Princeton,NJ:Princeton Scientific Publishing Co.,1988;133-158.

5. U.S. EPA. Science Advisory Board's review ofthe arsenic issues relating to the phase II proposedregulations from the Office of Drinking Water.EPA-SAB-EHC-89-038. Memorandum toWilliam K. Reilly. Washington, DC:Environmental Protection Agency, 1989.

6. Buchet JP, Lauwerys R, Roels H. Urinaryexcretion of inorganic arsenic and its metabo-lites after repeated ingestion of sodiummetaarsenite by volunteers. Int Arch OccupEnviron Health 48:111-118(1981).

7. Yamauchi H, Takahashi K, Mashiko M,Yamamura Y. Biological monitoring of arsenic

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exposure of gallium arsenide- and inorganicarsenic-exposed workers by determination ofinorganic arsenic and its metabolites in urineand hair. Am Ind Hyg Assoc J 50:606-612(1989).

8. Farmer JG, Johnson LR. Assessment of occu-pational exposure to inorganic arsenic based onurinary concentrations and speculation ofarsenic. BrJ Ind Med 47:342-348(1990).

9. Mohri T, Hisanaga A, Ishinishi N. Arsenicintake and excretion by Japanese adults: a 7-day duplicate diet study. Food Chem Toxicol28:521-529(1990).

10. Chen CJ, Kuo TL, Wu MM. Arsenic and can-cers (letter). Lancet i:414-415(1988).

11. Wu M-M, Kuo T-L, Hwang Y-W, Chen C-J.Dose-response relation between arsenic con-centration in well water and mortality fromcancers and vascular diseases. Am J Epidemiol

130:1123-1132(1989).12. Tseng W-P. Effects and dose-response relation-

ships of skin cancer and blackfoot disease witharsenic. Environ Health Perspect 19:109-119(1977).

13. Tseng W-P, Chu H-M, How S-W, Fang J-M,Lin C-S, Yen S. Prevalence of skin cancer in anendemic area of chronic arsenicism in Taiwan.] Nati Cancer Inst 40:453-463(1968).

14. Integrated Risk Information System (IRIS).U.S. EPA's on-line database of toxicity infor-mation. Washington, DC:EnvironmentalProtection Agency, June 1993.

15. Lu F-J. Blackfoot disease: arsenic or humicacid? (letter). Lancet 336:115-116(1990).

16. Lu F-J, Guo H-R, Chiang H-S, Hong C-L.Relationships between the fluorescent intensityof well water and the incidence rate of bladdercancer. J Chin Oncol Soc 2:14-23(1986).

17. Yang T-H, Blackwell RQ. Nutritional andenvironmental conditions in the endemicblackfoot area. Formosan Sci 15:101-129(1961).

18. National Research Council Subcommittee onthe tenth edition. Recommended dietaryallowances, 10th revised ed. Washington,DC:National Academy Press, 1989.

19. Valberg PA, Carlson-Lynch H, Beck BD.Arsenic skin cancer slope factor recalculationusing reference dose exposure parameters.Presented at the International Conference onArsenic Exposure and Health Effects, NewOrleans, Louisiana, 28-30 July 1993.

21. Guo H-R, Chen C-J, Chiang H-S, Hu H,Lipsitz SR, Monson RR. Arsenic in drinkingwater and urinary cancers: a preliminary report.Sci Technol Lett (in press).

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