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benefit analysis for toxic chemicals
ECOTOXICOLOGY
AND
ENVIRONMENTAL
Risk/Benefit
4, 370-383
SAFETY
Analysis
For Toxic Chemicals’
RICHARD Energy
and Environmental Hurwrd UtGwrsitp,
(1980)
WILSON
Policy Center nnd Department Cambridge. Massachusetts
Received
March
of‘ Physics. 02138
26, 1980
I am a layman as far as uses of chemicals are concerned. Therefore you will find my comments incomplete. But I believe that by looking at the field from outside, I can see the logic in comparing risks and benefits and ask questions; I may get answers which may seem obvious to you experts, but which I and other members of the public have not yet heard or understood, or if we have heard them, have ignored. First, it is obvious that some chemicals are risky. Some of them are toxic and others are designed to affect-even to destroy-one biological system and it is inconceivable to me that there is no effect on another (man) at some dosage level. Thus it has been said that all chemicals are toxic-it only depends on the dose. Second, I will concentrate on carcinogenic effects. There are, of course, obvious toxic effects of many of the chemicals which make us take care at high doses. But it is generally believed-and I share this belief-that the toxic effects at low doses are zero, and that an appropriate safety factor to take account of different individual sensitivities is enough. But there is a growing body of opinion that believes that the adverse effects of carcinogens may not be zero at low doses and that the risk may be proportional to the dose (exposure). An entirely different procedure for discussing safety is then necessary. Not only must we protect industrial workers and the principal users of whom a few get high doses-but we must protect the millions in the general population who are exposed to miniscule doses. For them the individual risk is low, but the total impact on society becomes appreciable when we multiply the small individual risk by the millions of the population exposed. In this I suggest we look at the precedents created in radiation control and measurement where this issue has been faced since 1920. From the earliest days it was known that X rays cause skin cancer and in the 1920s it was found that radiation causes leukemia and in the 1930s and 1940s it was found that radiation causes a host of other cancers too. In the 1920s physicians pointed out the huge benefits of rapid diagnosis by use of X rays, and said that the benefits outweigh any conceivable risk due to the X rays. Of course they were right, just as I believe you can make an excellent case that the benefits of most industrial chemicals outweigh the risks. In this simple risk benefit comparison, it is useful to list those items measured in the same units. A new chemical can save lives-by shortening a dangerous production process for example-and these can be compared directly with lives at risk from carcinogens. But the overall comparison of risk and benefit and the assurance that benefit 1 Presented Environmental
at the Quality.”
6th
“Chemical International Symposium September 17. 1979, Munich-Neuherberg.
0147-6513/80/040370-14$02.00/O Copyright All rights
0 1980 by Academic Press, Inc. of reproduction in any form reserved.
370
and
Toxicological
Aspects
of
TOXIC
CHEMICAL
371
ANALYSIS
exceeds risk is only the first question in a risk/benefit approach. To return to our analogy in the 192Os, it was pointed out that the same benefit of rapid diagnosis by use of X rays can be achieved with less risk: more sensitive X ray film, image intensifiers, shielding against stray X rays. We can then ask the question, how much effort or money should we spend to reduce the risk? We clearly cannot spend the whole gross national product on each and every risky chemical and we therefore need some yardstick. For those chemicals used as pesticides the analogy is that we might use a less risky pesticide or be careful how we spray it. This is important; it was the main emphasis (as I read it) of Rachel Carson’s Siletzt Spring and the main thrust of present regulatory activity. The International Commission on Radiological Protection (ICRP) was set up in 1928 to address these questions. Its reports have been published by Pergamon Press, and its prestige has been such that most countries of the world have passed its recommendations into regulation and law. Over the years, they have come up with useful phrases. “No exposure should be accepted ,without expectation of benefit.” “ It is prudent to assume that radiation causes cancer with an incidence or probability proportional to dose.” “Radiation exposure should be reduced to a level As Low As Practicable” (ALAP) (although this last phrase has been so shop worn that it is now replaced by “As Low As Reasonably Achievable, technical and economic considerations taken into account). This insistence on the idea that radiation may cause effects at low doses does tzot mean that ICRP or its members either belirve or disbeliet,e the proportional relation. Nor did it stop them from recommending statzdwds for radiation exposure.. for ordinary men and ordinary regulators to use. Merely that care must be taken even at levels be/oMl these standards.
Risk
for workers Inhalation Dermal
Mitigate Mask Gloves Caution Enclose
Benefit Job
Monitoring Trace measurements Blood Urine
in handling process
Public risk Water Air Food
Benefit Plastics Cheap food,
Mitigate Put industry downwind Use care in Food Water Stop smoking
Monitor Concentrations Air Water
FIGURE
1
etc
in
in
372
RICHARD
WILSON
For chemicals there are two separate groups to protect: workers and public. Conventionally workers are allowed more exposure than the public (for radiation-5 rem/year vs 0.17 rem/year) because there are fewer of them. In Figure 1 I outline the procedures for a risk/benefit comparison. For workers the only obvious benefit of producing toxic chemicals or using them is theirjob; but it is a large benefit. The analogy of chemicals with radiation tends to break down when we discuss monitoring; there is no simple device for measuring exposure to toxic chemicals analogous to the film badge carried by radiation workers which measures radiation exposure. At the moment the only check on exposure is an ex post facto measurement of concentration in blood or urine. 1 regard the development of some method of integral monitoring of exposure to carcinogenic chemicals as very important for sensible regulation. The rest of my discussion will be about risks and not about benefits. This is partially because I don’t know the benefits well, and partially because they are probably large enough that we are concerned with getting the same benefit for less risk. This leads up to a risk/risk comparison. I belabor this point because a TV tape in circulation states a belief that comparison of risks suhverfs risk/benefit analysis; it does not: it is a part of the whole process and a necessary part. In Fig. 2 I show the standard cancer assessment procedure. Although this is my figure, I believe it represents the scientific bases recommended by the Interagency Regulatory Liaison Group of the U.S. government ( 1). cowDOSE TESTS
HIGHDOSE LEVEL
HUMAN EPlDEMiOLOGY
INIMI\L
INCLUDING + OCCUP!aTIONAL
TESTS i POTENCY HIGH
AT DOSES
*
HlGH
DOSES
ii AT DOSES
/ COMPARE
AVERAGE
COMWRlSON
8
UNCERT41NTY
/
IN
LlMlTS MEDICAL
1 POTENCY
1
DOSE-
UPPER
METABOLIC
RESPONSE
STUDIES I i
SELECTED DERIVATION
CASES
OF
HIGH
DOSE POTENCY IN MeiN (WITH “NCERTIlNTY I
‘\ \
1 ASSUME
DOSE-RESPONSE
~PROPORTlON4L OTHER
MODIFY
BY
“NLESS---MET*!3OLIc
INFORMe;TION, I
CUT.4
i
ESTIMATE B
+
FEN&AL mP”LAT,ON
RISK
PROCEDURES
UNCERTAINTY
~COMEINING
GL;TTONOUS
OCCUPATIONAL
\ ESTIMATE
CONSUMERS
FROM
i
i
COMPARE F&ED
TO BY
THE
OTHER
/ RISKS
INDIVIDUAL
2. The “standard”
POTENCY
EXPOSURE-
E G ,
CHEM1Cc.L
FACTORY
EXPLOSION
FIG.
i UNCERTCllNTY
/ DIS&TROUS
INCLUDE
cancer
assessment
FOR UNCERTAINTIES
ONLY \ COMPARE
TO
RlSKS
FACED
SOCIETY HAIL,
procedure
OTHER
(DAMS,
EXPLOSIONS)
BY
TOXIC
CHEMICAL
ANALYSIS
373
We have only 26 chemicals directly proven to cause cancer in man-a dozen or so each from occupational exposures and from medical drugs. Each of these chemicals represents a mistake or set of mistakes that mankind has made in its ignorance. We do not want to repeat these mistakes for every chemical, so we must obtain as much information as possible from animal data and use analogy to derive the sensitivity of man. The data we have both in animal and man are at high doses. Therefore. we must decide how to proceed to low doses. Some of the best data on animal carcinogenesis come from feeding vinyl chloride monomer to rats for 4 hriday, 5 days/week for a year and observing them for the rest of the 2-year life. One of the advantages of this set of data is that vinyl chloride produces a very rare type of liver cancer, liver angiosarcoma, and the background of these cancers produced by other causes is low. I show in Fig. 3 some data from Maltoni at Bologna (2). The lines are the statistical error bars corresponding to N”“, where N is the number of rats getting cancer. They fit the linear, proportional model. The line is the fit by the EPA’s carcinogen assessment group (3). This is in accordance with another rule of mine: always take the government position ifit isn’t too far from your own or otherwise makes no difference. The background is low because liver angiosarcoma is a rare tumor. However, the data could fit either one of the two other curves shown; the bottom one, with much lower incidence of cancer at low doses, or the top one with much higher incidence. The experimental data-which cost several million pounds and eurodollars to acquire---cannot distinguish and to improve the statistical error another factor of 10 is impractical. Therefore we can only distinguish by theory. Some people believe the lower curve (the Mantel-Bryan log probit model or the Jones-Grendon long latent time model) but no serious person seems to propose the top curve, so in this sense the linear, proportional model is a conservative upper limit. In a cowzparison of chemicals which dose response we take makes no difference if both chemicals have the same dose-response relation. Moreover, in a close decision, we can always look more closely to decide which dose response to use. I now want to address the more important uncertainty-how to go from animal data to m,an. Some people used to say that if a chemical is found to be carcinogenic
. SERIES BTI 0 LATER SERIES x INGESTION
4hr/doy,
FIGURE
Sday/wh
3
for ,yr
374
RICHARD
POTENCY
WILSON
IN
66C3FI
FIGURE
MOUSE
(mg- kgdi
4
in animal it must be banned completely. This, I believe, is unnecessarily pessimistic and gets us into trouble because there are so many carcinogenic chemicals and we can’t ban them all. Nowadays we recognize in addition to differences in exposure that chemicals have different carcinogenic potency. Aflatoxin is a million times more potent than saccharin, and if we all put aflatoxin in our coffee the way we use saccharin, the expectation of life would drop to 40 years and we would all die of liver cancer. In most cases it appears that if a chemical is potent in one species it is potent in another. To test this, Crouch and I(4) took a recent set of animal cancer studies with the standard NC1 protocol and compared them. These chemicals werefed to the animals in regular amounts every day for life. In Figs. 4 and 5 we show some of our results. The potency as measured in the male and female of the same species are similar; women libbers will be happy with this, but those who sell Virginia Slims must be wary. The units in these figures are perhaps confusing. If animals fed W times D ( WD) mg of chemical for every day of its life, where W is the body weight in kilograms, and the incidence of cancer is P (P < 1) thenPIWD is called thepotency (P). This is the slope of the line in Fig. 3. In the comparison of rats and mice there are some notable exceptions; parathion-a pesticide-is 300 times more sensitive in the rat than in the mouse. This would make me wary about using these data to predict human potency for this chemical. We should look at metabolism; if the chemical dissolves in water we might expect that after ingestion it can go freely round the body of any species. For an insoluble compound this interspecies comparison may not work. I would also like to see a study on a third animal-preferably a primate even though we have to wait 7 years for the full lifetime incidence of cancer to be apparent. That metabolism of the animal is important is shown in Fig. 6 where I examine the high-dose region of Maltoni’s data on vinyl chloride. At no dose is the lifetime incidence of tumors more than 40% and the liver angiosarcomas are only half that
TOXIC
CHEMICAL
I ;; lo-‘P :rn E 10-z ,” 2 ? z
4 8
I
I /
//
,+’
’ + / /+ + + +A+/+ + / /+ + t +
lo-3-
+ 4+++
+
+
FISCHER RAT
344
+
+/ / ++
/
w-
!
/ //
y % b-l IL
CT
315
ANALYSIS
/ / -/ / I 10-q
10-5 / 10-s
I
PO?&3 ,
IN I;-;LE 1
I s
lo-‘-
;rn E +
I
I
(r~,-~t; I +
+ Porathlon
2 ix
,”
MALE
+ Acetotrexamide I
d)
’ /
I -
/+ /+ /++
Dloxath~on
/
+
IO~Z-
/
2
/’
+
/
+
/ ,‘++
=1 z 10-3-
/+
-
+
+/ /
L F g
++’ / lo+-
+
-
/ /
/ / 10-s.
’ D5
MOUSE
/ I I oIN 86C3FI
1 10-4 POTENCY
FIGURE
I lO-2 MOUSE
I I6 (mg-‘kgd)
I 1
5
-Y OCCUPATIONAL /i
/wEi
I SATURATION EXPLAINED /BY GEHRiNG i
.
SERIES
BTI
0
LATER
SERIES HIGHEST
ODOR BECOMES OBSERVABLE
OVER 103,ooO
I 5,oCQ CONCENTRATIONS ilhr/day, 5 day/v&
FIG.
6. Matoni’s
1 r
for
ppm I yr
rat data
wrn
376
RICHARD
WILSON
(20%). Yet a simple model would suggest P = {I - exp(-PD)} = PD at low doses and =I at high doses. Why do not 100% of animals have tumors at high doses? The correct explanation is probably that of Gehring and others of Dow Chemical Company (5) who point out that the production of the carcinogenic metabolite saturates and that if cancer incidence is plotted against metabolite concentration a straight line plot is obtained as the three high-dose points are shifted to the left. Maybe a future study of the metabolites can also prove a nonlinearity at the low doses also, leading to a lower risk than proportionality predicts. Many people believe this but it cannot be proven. There are also uncertainties due to synergisms. It is now widely believed that cancers have a multiple etiology; the simple proportionality of risk with dose must be replaced by a more complex relation, perhaps by a proportionality to each of several pollutants: P = PAP,P,....PS. These could, for example, be described by the Doll- Armitage model. We appear to have synergisms between radiation and smoking alcohol and smoking asbestos and smoking vinyl chloride and alcohol
human data animal data
In each of these cases, the synergism is seen only with large doses of each pollutant. With large doses of only one pollutant, the risk is not much increased. The causes of the cancer in addition to the pollutant considered are presumably general background, foodstuffs, radiation, and chemicals. There are cases in animal studies where larger synergisms are found. But these seem to be cases where one chemical aids in the absorption of another, in dermal contact. With these uncertainties in mind, we compare those cases where there is 103 -
/ /
102 ;; --
10’ E
$
/
+Arssnic
-
4y
/‘H
/ ‘-
//’
,-
z * ro-’ M -e ‘i” E a 10 -
y,,‘/’
+,//’ /
,03 -
T/i/ /
10-4
+
1 10-3
I 10-z
I 10-l POTENCY
FIGURE
I I I 1 10’ 102 IN RAT (mg-’ kg d)
7
I 103
TOXIC
CHEMICAL
FIGURE
ANALYSIS
377
8
carcinogenic potency in animal and man. The data here are not so good, but the general argument still holds; it is shown in Figs. 6 and 7. I point out nrserzic which is not an organic chemical, but nonetheless a common pesticide. It is only known to be carcinogenic in man, strongly so by inhalation and more weakly so by ingestion. The upper limit on carcinogenic potency in rats and mice is 1000 times less. The searches for animal carcinogenesis have been by ingestion or dermal contact, so this may be the difference. But there may be a different mechanism of carcinogenesis for heavy elements, and I assume proportionality in what follows anyway. These comparisons suggest, but certainly do not prove, that if a chemical is found to be a weak carcinogen in rats and mice, it is likely to be a weak carcinogen in man and not CI potent one. This leads to the suggestion that we need not concern ourselves with weak carcinogens to which we have low exposure; we must concern ourselves with potent carcinogens even if the exposure is low (aflatoxin) and weak carcinogens if the exposure is high (saccharin). Of course high exposure to potent carcinogens must be avoided completely. This suggestion is made quantitative by a risk analysis where we set the lifetime risk of getting cancer equal to the average daily exposure or dose. We must use caution in using this procedure of going from animal to man and keep our eyes open for exceptions. Another good argument for proportionality even if there is no proportionality in the basic mechanism of cancer because of metabolic effects is the possible additivity of dose when two agents cause the same cancer in very similar ways. This is illustrated in Fig. 8. Let us assume that air pollution and cigarette smoke do so. Then suppose the real dose-response relation is the red (curved) line. Air pollution hy itself might produce few cancers as shown by the extreme left-hand corner, but added to 1he large effect of cigarette smoking the effects is seen (in this case) to be 10 times larger. Since we have 350,000 cancers per year from all causes, and we are trying to reduce this 100 or less at a time, this may well be the usual situation. When it comes to public exposures the difference between a proportional model and one with a threshold is between an adverse health effect and no health effect (6). I assume therefore the proportional model, because I wisk to be moderately cautious and not to unnecessarily underprrdict the risk. But there is a simplicity about the proportional model which cannot be repeated too often. If I have an
378
RICHARD
Production Chemical
name
Trichloroethylene NTA (until 1970) Tetrachloroethylene Tetrachloroethane Trifluralin Tris (or TBP) 2.4-Diaminoanisole sulfate 1.2-Dichloroethane 1,4-Dioxane 1,2-Dibromoethane Dicofol Saccharin Benzene Produced Emitted Aflatoxin Aldrin Chlordane Dioxin
Arsenic DDT Parathion Dieldrin Heptachlor Endrin Benzo(a)pyrene Food Air Nuclear waste Ingestion
WILSON
Potency (mgm’ kgd)
(Fit)
Cancer dose W
Total potential No. of cancers (year’)
2.5 7.5 3.4 2 1.2 1.5
x x x x x x
10” 10”’ 10” 10” 10’0 lo”
0.0001 0.0002 0.001 0.004 0.0004 0.01
1.5 8 1.5 4 5 1.6
x x x x x x
10’ 10fi 10” lo” 10” 10”
1.6 8 2 4 2 8
x x x x x x
IO’ lo” l@ 104 lo” lo”
1.5 4.5 8 1.6 2 3
x x x x x x
107 10” 109 IO” log 10”
0.0008 0.003 0.001 0.5 0.003 0.0004
2 6 1.6 3 5 6
x x x x x x
10” 105 10” 10” lo” 10”
7 5 5 3 4.6
6.4 x x x x x
10” 10” 10’ lo” IO?
1.8 x 10” 1.8 x IO6 1.8 3.3 x 103 1.0 x 104 4 x 10-l
2.7 1.4 9.4 2.3 2.9 1.3
x x x x x x
10fi lo” lo:’ lo” lo” 104
4.8 x 10” 2.5 x 10” 1.7 x 10’ 8 x 10H 3 x 10” 4.5 x lo:’ (Seveso) 3.0 x 102 (2-4-ST) 2.0 x 10”’ 2.0 x 10”’
0.001 0.001 1000 0.5 0.2 5000 5000 15
-
3.0 x 10” 1.0 x lo” After 10 years After 500 years FIG. 9. Prepared
by L. Klein
4 x 10-I
8 x lo’
1.0 x lo? -
1.5 Y 10” -
0.1 0.4 0.5 0.9
2.0 5.0 4.0 2.0
7.0 7.0 -
2.5 x 102 2.5 x 102
and E. Crouch
x x x x
-
104 10” 103 lo:’
1.2 4.0 8.0 1.0
x x x x
10’ 105 10”’ 107
(1979).
amount of carcinogen and put it evenly into 100 peoples’ cocktails, 10 might develop cancer. If the same amount is fed to a million people, still only 10 people get cancer and this is independent of the way the pollutant is distributed. It becomes useful, therefore, to compare chemicals by the total number of cancer doses produced, manufactured, or imported each year. We show this in Fig. 9, prepared by E. Crouch and L. Klein. The potency is derived from the data of Crouch and Wilson and the cancer dose is the total amount of chemical which has to be fed to man (70 kg) in his lifetime (365 days/year x 70 years) to get cancer (actually the point where the straight line relating cancer incidence to dose at low doses reaches 100% incidence). The cancer dose in grams is then 365 x 70 x 70 potency X IO6 *
TOXIC
CHEMICAL
ANALYSIS
379
Then the total potential number of cancers per year is the production divided by the cancer dose. If man ate or drank all the chemical, this would be the cancers per year. For saccharin almost all the chemical is in fact drunk and this number (460iyear) is close to the official figure of the expected cancer incidence (actually a slightly more conservatllve way in going from animal to man was used by FDA). It must be remembered that if we assume a threshold in the dose-response relation the number drops down below this. We must remember also the major uncertainty of whether, in the cases where only animal data exists, we have the right procedure in deriving the potency in humans. I note 7’ L.,4-dianinoanisole (2,4-DAA)-a hair dye coupler. If we all drank hair dyes, six cancers per year would result. Fortunately most people put dye on their hair, not in their stomachs, so the numberofcancers are less. Fortunately, also. hair dye manufacturers are acting responsibly to remove 2,4-DAA from their products. The total potential number of cancers per year is not the whole story. Of course we must allow for dispersion, dilution, and disintegration of the chemical. These will vary from chemical to chemical and use to use. As a layman, I haven’t done this systematil:ally. but I note a few random points. Arsenic lasts forever-and may be carcinogenic in whatever chemical form it appears. ,4 recent study shows that arsenic dust is widely spread (probably from burning of fossil fuels) and on this proportional model, therefore, can be giving 50 lung cancers a year-a number too small to either confirm or deny in any direct way. The nuclear waste decays in a well-known way, and the numbers here are that waste which would be produced by all U.S. electric power ifall U.S. electric power in the year 2000 were nuclear. There is an important difference between the proper ways of handling nuclear and chemical wastes which is not always appreciated, that figure 9 brings out. If we isolate nuclear waste from the environment it decays. If we isolate chemical waste from the environment it stays the same. We need to render chemical waste innocuous either by interaction with the environment or by chemical action. The comparative smallness of some of the numbers for total cancers must be noted. We don’t all die of arsenical cancers even though the potential number is 10X/year. A study by Fraumeni and Blot suggested that 30iyear get lung cancer near smelters so a dilution seems to occur. It would seem that this dilution would prevent any&/it. hazard from most chemicals if the number of potential cancers is IO’ times less than arsenic-or less than lO.OOO/year. How do we assess the public risk reliably? For individual members of the public around a chemical plant we can calculate the dispersion-and this gives a fairly reliable long-term average concentration, and it is this average that is important for low-level effects. A better way might be to measure the concentrations of the carcinogen in blood or urine of a random sample of people and average over the sample. IJnfortunately, the sensitivity is not yet enough to rigorously prove by this method, that the risk is yet low enough. Finally, I list several in Fig. 10. 11. 12. and 13-risks of ordinary life which I prepared a year ago for an OSHA hearing (7). I have assigned a large uncertainty factor to the cancer risks; a factor of 3 when data are available from human epidemiology, and higher when only animal data are used. What do we do with these numbers? First, a worker might reasonably be asked, as a condition of his job, to undertake a risk no greater than the average risk in his line of wo,rk. A coal miner can, should, and now does, object to the high black lung
380
RICHARD
WILSON
No. of deaths in 1975 Football Automobile racing Horse racing Motorcycle racing Powerboating
Averaged over participants
Boxing (amateur) Skiing Canoeing Rock climbing (U.S.)
40 hriyear engaged in sports
4 I.2 1.3 1.8 1.7
300,000 cases
(drowning)
Averaged fishing
over licenses
Drowning (all recreational causes) all over U.S. Bicycling (assuming one person per bicycle) FIG.
IO. Risks
in sports
(see Ref.
FIG. curacy
II. Commonplace and therefore approximately 30%.
accepted
risks
10-s IO :I IO-,’ IO-:’ IO-’
5 x 10-3
343
I.0 x IO-;’
4110 1000
1.9 x IO-5 , o-.5
(8)).
No.
Motor vehicle (in 1975) Total Pedestrian (certainly involuntary) Home accidents (1975) Alcohol Cirrhosis of the liver (1974) Cirrhosis of the liver (moderate drinker) Air travel One transcontinental trip/year Jet-flying professor Accidental poisoning Solids and liquids Gases and vapors Inhalation and ingestion of objects Electrocution Falls Tornados (average over several years) Hurricanes (average over several years) Lightning (average over several years) Air pollution Total U.S. estimate (sulfates) Urban U.S. (benzo(cu)pyrene)-cancer risk Vaccination for smallpox (per occasion) Living for I year downstream of a dam (calculated)
x Y x x x
2 x lo-” 3 x 10-S 4 x IO-’ ,o-”
Sunbathing, mountain climbing (skin cancer risk/curable) Fishing
Risk/years
of deaths in 1974
Risk/year
46,000 8,600 25,500
2.2 x 10-J 4 x lo1.2 x 10-5 1.6 x IO-” 4 x IOF 3 x 10-6 IO-’
of death
1,214 1.518 2,991 1,157 16,339 160 II8 90
6 7 I.4 5 7.7 5 4 4
x x x x x x x x
30.000
1.5 3 3 5
x 10-d x lo-” x 10-h x lo-”
(noncancerous)
(see Ref.
IO-” 10-e 10-s lo-” 10-5 10-T 10-7 10-T
(9)).
Ac-
TOXIC
CHEMICAL
381
ANALYSIS
incidence. Society is divided on how it should deal with saccharin. It is voluntary, and the risk is borne by the person who perceives the benefit. Nonetheless diet sodas are culturally habit forming and society has a duty to protect members from themselves and is acting to discourage cigarette smoking. The comparatively large calculated societal impact of saccharin (460iyear) is much larger than l/50 years from use of2,4-DAA in hair dyes, so it is hard for the Food and Drug Administration to act to restrain the second use if it does not restrain the first. When replacing one chemical, known to be carcinogenic, by another it seems to me important to measure the carcinogenicity of the substitute chemical; or to put an upper limit on its carcinogenicity if the sensitivity of the study is limited. The substitution should only be made if one is reasonably sure that the risk is reduced and one is not merely jumping from the frying pan into the fire. If these calculational procedures are followed, I believe that one can have reasonable guides on whether and how to use what chemicals. In the last 2 years I
Risk/year Cosmic ray risks One transcontinental flight/year Airline pilot SO hrimonth at 35.000 ft Frequent airline passenger One summer (4 months) camping at 15.000 Living in Denver compared to New York
feet
Other radiation risks Average U.S. diagnostic medical X rays Increase in risk from living in a brick building bricks) compared to wood Natural background at see level
]O-”
(with
Eating and d.rinking One diet soda (saccharin) Average IJ.S. saccharin consumption 4 tb peanut butter/day (atlatoxin) One pint milk per day (aflatoxin) Miami or New Orleans drinking water (chloroform) 9 lb charcoal broiled steak once a week (benzopyrene) risk only: heart attack. etc. additional) Alcohol Averaged over smokers and nonsmokers Light drinker (one beer/day) Tobacco Smoker Cancer only All effects (including heart Person in room with smoker
pills regularly
FIG.
I?. Commonplace
risks
of daily
3
radioactive 3 3 , 0.. 3
I.2 \( IO ti
10 I0 3 3 5
4 x 10-T
IO
2 z. IO-” 4 ‘.: ] o-” 10-5 (cancer
3 3
disease)
Miscellaneous Taking contraceptive
Estimated uncertainty (factor of 3)
life (cancer
risks)
1.’ x 10-i’ 3 x 10-z ] O-5
3 3 IO
2 x lo-”
IO
(see Ref. (7))
382
RICHARD
WILSON
Number of fatalities (in 1975 unless stated) Mining and quarrying (accident only) Coal mining Accident (average 1970- 1974) Black lung disease (1969) Agriculture Total Tractor driver (one driver/tractor) Trade Manufacturing Service Government Transportation and utilities Airline pilot Truck driver (one driver/truck) Jet-flying consultant and professor Steel worker (accident only) (1969- 1971) Railroad worker (1974) (all accidents excluding Fire fighters (1971- 1972 average) FIG.
13. Current
occupational
risks
500
6 Y IO-’
180 1135
1.3 x lo-” 8 x 10-Z’
2100
6 x 10m4 1.3 x IO-4 6 x lo-’ 8 x lo-” 9 x 10-j 1.1 x IO-4 3.3 x lo-” 3 x IO-’ 10-4 1 o-4 2.8 x lo-” 1.3 x 10-R 8 x 10m4
I200 1500 1800 1100 1600 400
grade
crossing)
(see Refs.
(7.8.10)).
66 688
Accuracy
Risk/year
approximately
30%
have noticed a change in the public discussion of these issues, stimulated, no doubt, by the saccharin and nitrite cases. I think both regulatory agencies and the public are now willing to accept these numerical estimates, and have recognized that the search for zero risk is illusory. Finally I may seem like a fool rushing in where angels fear to tread. But the public and politicians demand answers. If experts don’t give answers the politicians will ask me. If I don’t give answers, the politicians will ask someone who knows even less. We nzusr give answers-suitably, but not too liberally, qualified with the uncertainties. ACKNOWLEDGMENTS This work has inputs from various sources; the comparisons of potency done by Dr. Edmund Crouch and Ms. Leslie Klein were funded by a grant from the Cabot Foundation with additional funding on comparison to nuclear power from the nuclear Regulatory Commission. Ms. Diane Rolinski typed innumerable manuscripts and tables from which these pages were selected.
REFERENCES 1. Federal Register 44. No. 131. p. 39.858. July 6. 1979. 2. MALTONI. C.. et cl/. (1974). “Vinyl Chloride Carcinogenesis: Current Results and Perspectives.” Ltr Medici/ie drl Ln\ww 65, 421 3. KUZMACK. A. M.. AND MCGAUGHY, R. E. (1975). Q~crrrrircrtirr Risk, A.ssc~srnenrf;w Commrrttity Erpo.rrrre to Viny/ Chloride. EPA report, December 5. 4. CROUCH. E. A. C.. AND WILSON. R. Interspecies comparison of carcinogenic potency. J. To.~ico/. Eti~~iuon. Hmlti~ 5, 1095 (1979).
TOXIC
8.
9.
IO.
ANALYSIS
383
R. J.. WATANABE, P. G.. AND PARK. C. N. (1978). Resolution ofdose-response data for chemicals requiring metabolic activation: example-vinyl chloride (Dow Chemical Company report I To.ric~~/. Appl. P hcrvmucd. 44, 58 I - 591 WILSON. R. (1978). Risks caused by low levels of pollution. rhle J. Biol. Med. 51. 37. WII SON. R. Testimony for OSHA hearing on the identification, classification. and regulation of toxic substances posing a potential occupational carcinogenic risk. U.S. Dept. of Labor April 1978. FERRIS. 13. G. (1963). N. Ehgl. J. Med. 268,430. Sowby. F. D. (1965). Hcc~lfh P/IX.\. 1 I, 879. Starr. C. ( 1969). Sc,iericc 165, 1232. Clarke, K. S. (1966). J. Amer. Mud. Assoc~. 197, 894. Sfc~ti.stic~c~/ B~~//ctrn, Metropolitan Life Insurance Co.. May 1977. National Safety Council ( 1976). Acc,idc,nr Fcrcfs. National Safety Council, Chicago. Strrtistictr/ .4hsrrrrc,r c:f’fllc U.S. ( 1976). National Safety Council ( 1976). Acc,idrrrt Fdc,f~\. Strrti.sfic~o/Ah.sfrrr~~/ c;f’tlrr U.S. (1976). Alcohol. see previous reference for details: Air travel. see previous reference for details: Air pollution. see previous reference for details: Dam failure. AYYASWAMY et (I/. (1974). UCLA report UCLAENG-7423. March. National Safety Council (1976). A~~~idt~ul Fr~r,t.s. pp. 23.87. For coal mining black lung. rail worker. steel workers, see BALDEWICZ. W.. c~f rri. (1974). UCLA-ENG-7485. November. For airline pilot. see Ref. (8). .Srrrr,,\fic~ct/ Ah.ctrtrct of the U.S., t 1976). Table 1200.
5. GEHRING.
6. 7.
CHEMICAL
AND
ENVIRONMENTAL
Risk/Benefit
4, 370-383
SAFETY
Analysis
For Toxic Chemicals’
RICHARD Energy
and Environmental Hurwrd UtGwrsitp,
(1980)
WILSON
Policy Center nnd Department Cambridge. Massachusetts
Received
March
of‘ Physics. 02138
26, 1980
I am a layman as far as uses of chemicals are concerned. Therefore you will find my comments incomplete. But I believe that by looking at the field from outside, I can see the logic in comparing risks and benefits and ask questions; I may get answers which may seem obvious to you experts, but which I and other members of the public have not yet heard or understood, or if we have heard them, have ignored. First, it is obvious that some chemicals are risky. Some of them are toxic and others are designed to affect-even to destroy-one biological system and it is inconceivable to me that there is no effect on another (man) at some dosage level. Thus it has been said that all chemicals are toxic-it only depends on the dose. Second, I will concentrate on carcinogenic effects. There are, of course, obvious toxic effects of many of the chemicals which make us take care at high doses. But it is generally believed-and I share this belief-that the toxic effects at low doses are zero, and that an appropriate safety factor to take account of different individual sensitivities is enough. But there is a growing body of opinion that believes that the adverse effects of carcinogens may not be zero at low doses and that the risk may be proportional to the dose (exposure). An entirely different procedure for discussing safety is then necessary. Not only must we protect industrial workers and the principal users of whom a few get high doses-but we must protect the millions in the general population who are exposed to miniscule doses. For them the individual risk is low, but the total impact on society becomes appreciable when we multiply the small individual risk by the millions of the population exposed. In this I suggest we look at the precedents created in radiation control and measurement where this issue has been faced since 1920. From the earliest days it was known that X rays cause skin cancer and in the 1920s it was found that radiation causes leukemia and in the 1930s and 1940s it was found that radiation causes a host of other cancers too. In the 1920s physicians pointed out the huge benefits of rapid diagnosis by use of X rays, and said that the benefits outweigh any conceivable risk due to the X rays. Of course they were right, just as I believe you can make an excellent case that the benefits of most industrial chemicals outweigh the risks. In this simple risk benefit comparison, it is useful to list those items measured in the same units. A new chemical can save lives-by shortening a dangerous production process for example-and these can be compared directly with lives at risk from carcinogens. But the overall comparison of risk and benefit and the assurance that benefit 1 Presented Environmental
at the Quality.”
6th
“Chemical International Symposium September 17. 1979, Munich-Neuherberg.
0147-6513/80/040370-14$02.00/O Copyright All rights
0 1980 by Academic Press, Inc. of reproduction in any form reserved.
370
and
Toxicological
Aspects
of
TOXIC
CHEMICAL
371
ANALYSIS
exceeds risk is only the first question in a risk/benefit approach. To return to our analogy in the 192Os, it was pointed out that the same benefit of rapid diagnosis by use of X rays can be achieved with less risk: more sensitive X ray film, image intensifiers, shielding against stray X rays. We can then ask the question, how much effort or money should we spend to reduce the risk? We clearly cannot spend the whole gross national product on each and every risky chemical and we therefore need some yardstick. For those chemicals used as pesticides the analogy is that we might use a less risky pesticide or be careful how we spray it. This is important; it was the main emphasis (as I read it) of Rachel Carson’s Siletzt Spring and the main thrust of present regulatory activity. The International Commission on Radiological Protection (ICRP) was set up in 1928 to address these questions. Its reports have been published by Pergamon Press, and its prestige has been such that most countries of the world have passed its recommendations into regulation and law. Over the years, they have come up with useful phrases. “No exposure should be accepted ,without expectation of benefit.” “ It is prudent to assume that radiation causes cancer with an incidence or probability proportional to dose.” “Radiation exposure should be reduced to a level As Low As Practicable” (ALAP) (although this last phrase has been so shop worn that it is now replaced by “As Low As Reasonably Achievable, technical and economic considerations taken into account). This insistence on the idea that radiation may cause effects at low doses does tzot mean that ICRP or its members either belirve or disbeliet,e the proportional relation. Nor did it stop them from recommending statzdwds for radiation exposure.. for ordinary men and ordinary regulators to use. Merely that care must be taken even at levels be/oMl these standards.
Risk
for workers Inhalation Dermal
Mitigate Mask Gloves Caution Enclose
Benefit Job
Monitoring Trace measurements Blood Urine
in handling process
Public risk Water Air Food
Benefit Plastics Cheap food,
Mitigate Put industry downwind Use care in Food Water Stop smoking
Monitor Concentrations Air Water
FIGURE
1
etc
in
in
372
RICHARD
WILSON
For chemicals there are two separate groups to protect: workers and public. Conventionally workers are allowed more exposure than the public (for radiation-5 rem/year vs 0.17 rem/year) because there are fewer of them. In Figure 1 I outline the procedures for a risk/benefit comparison. For workers the only obvious benefit of producing toxic chemicals or using them is theirjob; but it is a large benefit. The analogy of chemicals with radiation tends to break down when we discuss monitoring; there is no simple device for measuring exposure to toxic chemicals analogous to the film badge carried by radiation workers which measures radiation exposure. At the moment the only check on exposure is an ex post facto measurement of concentration in blood or urine. 1 regard the development of some method of integral monitoring of exposure to carcinogenic chemicals as very important for sensible regulation. The rest of my discussion will be about risks and not about benefits. This is partially because I don’t know the benefits well, and partially because they are probably large enough that we are concerned with getting the same benefit for less risk. This leads up to a risk/risk comparison. I belabor this point because a TV tape in circulation states a belief that comparison of risks suhverfs risk/benefit analysis; it does not: it is a part of the whole process and a necessary part. In Fig. 2 I show the standard cancer assessment procedure. Although this is my figure, I believe it represents the scientific bases recommended by the Interagency Regulatory Liaison Group of the U.S. government ( 1). cowDOSE TESTS
HIGHDOSE LEVEL
HUMAN EPlDEMiOLOGY
INIMI\L
INCLUDING + OCCUP!aTIONAL
TESTS i POTENCY HIGH
AT DOSES
*
HlGH
DOSES
ii AT DOSES
/ COMPARE
AVERAGE
COMWRlSON
8
UNCERT41NTY
/
IN
LlMlTS MEDICAL
1 POTENCY
1
DOSE-
UPPER
METABOLIC
RESPONSE
STUDIES I i
SELECTED DERIVATION
CASES
OF
HIGH
DOSE POTENCY IN MeiN (WITH “NCERTIlNTY I
‘\ \
1 ASSUME
DOSE-RESPONSE
~PROPORTlON4L OTHER
MODIFY
BY
“NLESS---MET*!3OLIc
INFORMe;TION, I
CUT.4
i
ESTIMATE B
+
FEN&AL mP”LAT,ON
RISK
PROCEDURES
UNCERTAINTY
~COMEINING
GL;TTONOUS
OCCUPATIONAL
\ ESTIMATE
CONSUMERS
FROM
i
i
COMPARE F&ED
TO BY
THE
OTHER
/ RISKS
INDIVIDUAL
2. The “standard”
POTENCY
EXPOSURE-
E G ,
CHEM1Cc.L
FACTORY
EXPLOSION
FIG.
i UNCERTCllNTY
/ DIS&TROUS
INCLUDE
cancer
assessment
FOR UNCERTAINTIES
ONLY \ COMPARE
TO
RlSKS
FACED
SOCIETY HAIL,
procedure
OTHER
(DAMS,
EXPLOSIONS)
BY
TOXIC
CHEMICAL
ANALYSIS
373
We have only 26 chemicals directly proven to cause cancer in man-a dozen or so each from occupational exposures and from medical drugs. Each of these chemicals represents a mistake or set of mistakes that mankind has made in its ignorance. We do not want to repeat these mistakes for every chemical, so we must obtain as much information as possible from animal data and use analogy to derive the sensitivity of man. The data we have both in animal and man are at high doses. Therefore. we must decide how to proceed to low doses. Some of the best data on animal carcinogenesis come from feeding vinyl chloride monomer to rats for 4 hriday, 5 days/week for a year and observing them for the rest of the 2-year life. One of the advantages of this set of data is that vinyl chloride produces a very rare type of liver cancer, liver angiosarcoma, and the background of these cancers produced by other causes is low. I show in Fig. 3 some data from Maltoni at Bologna (2). The lines are the statistical error bars corresponding to N”“, where N is the number of rats getting cancer. They fit the linear, proportional model. The line is the fit by the EPA’s carcinogen assessment group (3). This is in accordance with another rule of mine: always take the government position ifit isn’t too far from your own or otherwise makes no difference. The background is low because liver angiosarcoma is a rare tumor. However, the data could fit either one of the two other curves shown; the bottom one, with much lower incidence of cancer at low doses, or the top one with much higher incidence. The experimental data-which cost several million pounds and eurodollars to acquire---cannot distinguish and to improve the statistical error another factor of 10 is impractical. Therefore we can only distinguish by theory. Some people believe the lower curve (the Mantel-Bryan log probit model or the Jones-Grendon long latent time model) but no serious person seems to propose the top curve, so in this sense the linear, proportional model is a conservative upper limit. In a cowzparison of chemicals which dose response we take makes no difference if both chemicals have the same dose-response relation. Moreover, in a close decision, we can always look more closely to decide which dose response to use. I now want to address the more important uncertainty-how to go from animal data to m,an. Some people used to say that if a chemical is found to be carcinogenic
. SERIES BTI 0 LATER SERIES x INGESTION
4hr/doy,
FIGURE
Sday/wh
3
for ,yr
374
RICHARD
POTENCY
WILSON
IN
66C3FI
FIGURE
MOUSE
(mg- kgdi
4
in animal it must be banned completely. This, I believe, is unnecessarily pessimistic and gets us into trouble because there are so many carcinogenic chemicals and we can’t ban them all. Nowadays we recognize in addition to differences in exposure that chemicals have different carcinogenic potency. Aflatoxin is a million times more potent than saccharin, and if we all put aflatoxin in our coffee the way we use saccharin, the expectation of life would drop to 40 years and we would all die of liver cancer. In most cases it appears that if a chemical is potent in one species it is potent in another. To test this, Crouch and I(4) took a recent set of animal cancer studies with the standard NC1 protocol and compared them. These chemicals werefed to the animals in regular amounts every day for life. In Figs. 4 and 5 we show some of our results. The potency as measured in the male and female of the same species are similar; women libbers will be happy with this, but those who sell Virginia Slims must be wary. The units in these figures are perhaps confusing. If animals fed W times D ( WD) mg of chemical for every day of its life, where W is the body weight in kilograms, and the incidence of cancer is P (P < 1) thenPIWD is called thepotency (P). This is the slope of the line in Fig. 3. In the comparison of rats and mice there are some notable exceptions; parathion-a pesticide-is 300 times more sensitive in the rat than in the mouse. This would make me wary about using these data to predict human potency for this chemical. We should look at metabolism; if the chemical dissolves in water we might expect that after ingestion it can go freely round the body of any species. For an insoluble compound this interspecies comparison may not work. I would also like to see a study on a third animal-preferably a primate even though we have to wait 7 years for the full lifetime incidence of cancer to be apparent. That metabolism of the animal is important is shown in Fig. 6 where I examine the high-dose region of Maltoni’s data on vinyl chloride. At no dose is the lifetime incidence of tumors more than 40% and the liver angiosarcomas are only half that
TOXIC
CHEMICAL
I ;; lo-‘P :rn E 10-z ,” 2 ? z
4 8
I
I /
//
,+’
’ + / /+ + + +A+/+ + / /+ + t +
lo-3-
+ 4+++
+
+
FISCHER RAT
344
+
+/ / ++
/
w-
!
/ //
y % b-l IL
CT
315
ANALYSIS
/ / -/ / I 10-q
10-5 / 10-s
I
PO?&3 ,
IN I;-;LE 1
I s
lo-‘-
;rn E +
I
I
(r~,-~t; I +
+ Porathlon
2 ix
,”
MALE
+ Acetotrexamide I
d)
’ /
I -
/+ /+ /++
Dloxath~on
/
+
IO~Z-
/
2
/’
+
/
+
/ ,‘++
=1 z 10-3-
/+
-
+
+/ /
L F g
++’ / lo+-
+
-
/ /
/ / 10-s.
’ D5
MOUSE
/ I I oIN 86C3FI
1 10-4 POTENCY
FIGURE
I lO-2 MOUSE
I I6 (mg-‘kgd)
I 1
5
-Y OCCUPATIONAL /i
/wEi
I SATURATION EXPLAINED /BY GEHRiNG i
.
SERIES
BTI
0
LATER
SERIES HIGHEST
ODOR BECOMES OBSERVABLE
OVER 103,ooO
I 5,oCQ CONCENTRATIONS ilhr/day, 5 day/v&
FIG.
6. Matoni’s
1 r
for
ppm I yr
rat data
wrn
376
RICHARD
WILSON
(20%). Yet a simple model would suggest P = {I - exp(-PD)} = PD at low doses and =I at high doses. Why do not 100% of animals have tumors at high doses? The correct explanation is probably that of Gehring and others of Dow Chemical Company (5) who point out that the production of the carcinogenic metabolite saturates and that if cancer incidence is plotted against metabolite concentration a straight line plot is obtained as the three high-dose points are shifted to the left. Maybe a future study of the metabolites can also prove a nonlinearity at the low doses also, leading to a lower risk than proportionality predicts. Many people believe this but it cannot be proven. There are also uncertainties due to synergisms. It is now widely believed that cancers have a multiple etiology; the simple proportionality of risk with dose must be replaced by a more complex relation, perhaps by a proportionality to each of several pollutants: P = PAP,P,....PS. These could, for example, be described by the Doll- Armitage model. We appear to have synergisms between radiation and smoking alcohol and smoking asbestos and smoking vinyl chloride and alcohol
human data animal data
In each of these cases, the synergism is seen only with large doses of each pollutant. With large doses of only one pollutant, the risk is not much increased. The causes of the cancer in addition to the pollutant considered are presumably general background, foodstuffs, radiation, and chemicals. There are cases in animal studies where larger synergisms are found. But these seem to be cases where one chemical aids in the absorption of another, in dermal contact. With these uncertainties in mind, we compare those cases where there is 103 -
/ /
102 ;; --
10’ E
$
/
+Arssnic
-
4y
/‘H
/ ‘-
//’
,-
z * ro-’ M -e ‘i” E a 10 -
y,,‘/’
+,//’ /
,03 -
T/i/ /
10-4
+
1 10-3
I 10-z
I 10-l POTENCY
FIGURE
I I I 1 10’ 102 IN RAT (mg-’ kg d)
7
I 103
TOXIC
CHEMICAL
FIGURE
ANALYSIS
377
8
carcinogenic potency in animal and man. The data here are not so good, but the general argument still holds; it is shown in Figs. 6 and 7. I point out nrserzic which is not an organic chemical, but nonetheless a common pesticide. It is only known to be carcinogenic in man, strongly so by inhalation and more weakly so by ingestion. The upper limit on carcinogenic potency in rats and mice is 1000 times less. The searches for animal carcinogenesis have been by ingestion or dermal contact, so this may be the difference. But there may be a different mechanism of carcinogenesis for heavy elements, and I assume proportionality in what follows anyway. These comparisons suggest, but certainly do not prove, that if a chemical is found to be a weak carcinogen in rats and mice, it is likely to be a weak carcinogen in man and not CI potent one. This leads to the suggestion that we need not concern ourselves with weak carcinogens to which we have low exposure; we must concern ourselves with potent carcinogens even if the exposure is low (aflatoxin) and weak carcinogens if the exposure is high (saccharin). Of course high exposure to potent carcinogens must be avoided completely. This suggestion is made quantitative by a risk analysis where we set the lifetime risk of getting cancer equal to the average daily exposure or dose. We must use caution in using this procedure of going from animal to man and keep our eyes open for exceptions. Another good argument for proportionality even if there is no proportionality in the basic mechanism of cancer because of metabolic effects is the possible additivity of dose when two agents cause the same cancer in very similar ways. This is illustrated in Fig. 8. Let us assume that air pollution and cigarette smoke do so. Then suppose the real dose-response relation is the red (curved) line. Air pollution hy itself might produce few cancers as shown by the extreme left-hand corner, but added to 1he large effect of cigarette smoking the effects is seen (in this case) to be 10 times larger. Since we have 350,000 cancers per year from all causes, and we are trying to reduce this 100 or less at a time, this may well be the usual situation. When it comes to public exposures the difference between a proportional model and one with a threshold is between an adverse health effect and no health effect (6). I assume therefore the proportional model, because I wisk to be moderately cautious and not to unnecessarily underprrdict the risk. But there is a simplicity about the proportional model which cannot be repeated too often. If I have an
378
RICHARD
Production Chemical
name
Trichloroethylene NTA (until 1970) Tetrachloroethylene Tetrachloroethane Trifluralin Tris (or TBP) 2.4-Diaminoanisole sulfate 1.2-Dichloroethane 1,4-Dioxane 1,2-Dibromoethane Dicofol Saccharin Benzene Produced Emitted Aflatoxin Aldrin Chlordane Dioxin
Arsenic DDT Parathion Dieldrin Heptachlor Endrin Benzo(a)pyrene Food Air Nuclear waste Ingestion
WILSON
Potency (mgm’ kgd)
(Fit)
Cancer dose W
Total potential No. of cancers (year’)
2.5 7.5 3.4 2 1.2 1.5
x x x x x x
10” 10”’ 10” 10” 10’0 lo”
0.0001 0.0002 0.001 0.004 0.0004 0.01
1.5 8 1.5 4 5 1.6
x x x x x x
10’ 10fi 10” lo” 10” 10”
1.6 8 2 4 2 8
x x x x x x
IO’ lo” l@ 104 lo” lo”
1.5 4.5 8 1.6 2 3
x x x x x x
107 10” 109 IO” log 10”
0.0008 0.003 0.001 0.5 0.003 0.0004
2 6 1.6 3 5 6
x x x x x x
10” 105 10” 10” lo” 10”
7 5 5 3 4.6
6.4 x x x x x
10” 10” 10’ lo” IO?
1.8 x 10” 1.8 x IO6 1.8 3.3 x 103 1.0 x 104 4 x 10-l
2.7 1.4 9.4 2.3 2.9 1.3
x x x x x x
10fi lo” lo:’ lo” lo” 104
4.8 x 10” 2.5 x 10” 1.7 x 10’ 8 x 10H 3 x 10” 4.5 x lo:’ (Seveso) 3.0 x 102 (2-4-ST) 2.0 x 10”’ 2.0 x 10”’
0.001 0.001 1000 0.5 0.2 5000 5000 15
-
3.0 x 10” 1.0 x lo” After 10 years After 500 years FIG. 9. Prepared
by L. Klein
4 x 10-I
8 x lo’
1.0 x lo? -
1.5 Y 10” -
0.1 0.4 0.5 0.9
2.0 5.0 4.0 2.0
7.0 7.0 -
2.5 x 102 2.5 x 102
and E. Crouch
x x x x
-
104 10” 103 lo:’
1.2 4.0 8.0 1.0
x x x x
10’ 105 10”’ 107
(1979).
amount of carcinogen and put it evenly into 100 peoples’ cocktails, 10 might develop cancer. If the same amount is fed to a million people, still only 10 people get cancer and this is independent of the way the pollutant is distributed. It becomes useful, therefore, to compare chemicals by the total number of cancer doses produced, manufactured, or imported each year. We show this in Fig. 9, prepared by E. Crouch and L. Klein. The potency is derived from the data of Crouch and Wilson and the cancer dose is the total amount of chemical which has to be fed to man (70 kg) in his lifetime (365 days/year x 70 years) to get cancer (actually the point where the straight line relating cancer incidence to dose at low doses reaches 100% incidence). The cancer dose in grams is then 365 x 70 x 70 potency X IO6 *
TOXIC
CHEMICAL
ANALYSIS
379
Then the total potential number of cancers per year is the production divided by the cancer dose. If man ate or drank all the chemical, this would be the cancers per year. For saccharin almost all the chemical is in fact drunk and this number (460iyear) is close to the official figure of the expected cancer incidence (actually a slightly more conservatllve way in going from animal to man was used by FDA). It must be remembered that if we assume a threshold in the dose-response relation the number drops down below this. We must remember also the major uncertainty of whether, in the cases where only animal data exists, we have the right procedure in deriving the potency in humans. I note 7’ L.,4-dianinoanisole (2,4-DAA)-a hair dye coupler. If we all drank hair dyes, six cancers per year would result. Fortunately most people put dye on their hair, not in their stomachs, so the numberofcancers are less. Fortunately, also. hair dye manufacturers are acting responsibly to remove 2,4-DAA from their products. The total potential number of cancers per year is not the whole story. Of course we must allow for dispersion, dilution, and disintegration of the chemical. These will vary from chemical to chemical and use to use. As a layman, I haven’t done this systematil:ally. but I note a few random points. Arsenic lasts forever-and may be carcinogenic in whatever chemical form it appears. ,4 recent study shows that arsenic dust is widely spread (probably from burning of fossil fuels) and on this proportional model, therefore, can be giving 50 lung cancers a year-a number too small to either confirm or deny in any direct way. The nuclear waste decays in a well-known way, and the numbers here are that waste which would be produced by all U.S. electric power ifall U.S. electric power in the year 2000 were nuclear. There is an important difference between the proper ways of handling nuclear and chemical wastes which is not always appreciated, that figure 9 brings out. If we isolate nuclear waste from the environment it decays. If we isolate chemical waste from the environment it stays the same. We need to render chemical waste innocuous either by interaction with the environment or by chemical action. The comparative smallness of some of the numbers for total cancers must be noted. We don’t all die of arsenical cancers even though the potential number is 10X/year. A study by Fraumeni and Blot suggested that 30iyear get lung cancer near smelters so a dilution seems to occur. It would seem that this dilution would prevent any&/it. hazard from most chemicals if the number of potential cancers is IO’ times less than arsenic-or less than lO.OOO/year. How do we assess the public risk reliably? For individual members of the public around a chemical plant we can calculate the dispersion-and this gives a fairly reliable long-term average concentration, and it is this average that is important for low-level effects. A better way might be to measure the concentrations of the carcinogen in blood or urine of a random sample of people and average over the sample. IJnfortunately, the sensitivity is not yet enough to rigorously prove by this method, that the risk is yet low enough. Finally, I list several in Fig. 10. 11. 12. and 13-risks of ordinary life which I prepared a year ago for an OSHA hearing (7). I have assigned a large uncertainty factor to the cancer risks; a factor of 3 when data are available from human epidemiology, and higher when only animal data are used. What do we do with these numbers? First, a worker might reasonably be asked, as a condition of his job, to undertake a risk no greater than the average risk in his line of wo,rk. A coal miner can, should, and now does, object to the high black lung
380
RICHARD
WILSON
No. of deaths in 1975 Football Automobile racing Horse racing Motorcycle racing Powerboating
Averaged over participants
Boxing (amateur) Skiing Canoeing Rock climbing (U.S.)
40 hriyear engaged in sports
4 I.2 1.3 1.8 1.7
300,000 cases
(drowning)
Averaged fishing
over licenses
Drowning (all recreational causes) all over U.S. Bicycling (assuming one person per bicycle) FIG.
IO. Risks
in sports
(see Ref.
FIG. curacy
II. Commonplace and therefore approximately 30%.
accepted
risks
10-s IO :I IO-,’ IO-:’ IO-’
5 x 10-3
343
I.0 x IO-;’
4110 1000
1.9 x IO-5 , o-.5
(8)).
No.
Motor vehicle (in 1975) Total Pedestrian (certainly involuntary) Home accidents (1975) Alcohol Cirrhosis of the liver (1974) Cirrhosis of the liver (moderate drinker) Air travel One transcontinental trip/year Jet-flying professor Accidental poisoning Solids and liquids Gases and vapors Inhalation and ingestion of objects Electrocution Falls Tornados (average over several years) Hurricanes (average over several years) Lightning (average over several years) Air pollution Total U.S. estimate (sulfates) Urban U.S. (benzo(cu)pyrene)-cancer risk Vaccination for smallpox (per occasion) Living for I year downstream of a dam (calculated)
x Y x x x
2 x lo-” 3 x 10-S 4 x IO-’ ,o-”
Sunbathing, mountain climbing (skin cancer risk/curable) Fishing
Risk/years
of deaths in 1974
Risk/year
46,000 8,600 25,500
2.2 x 10-J 4 x lo1.2 x 10-5 1.6 x IO-” 4 x IOF 3 x 10-6 IO-’
of death
1,214 1.518 2,991 1,157 16,339 160 II8 90
6 7 I.4 5 7.7 5 4 4
x x x x x x x x
30.000
1.5 3 3 5
x 10-d x lo-” x 10-h x lo-”
(noncancerous)
(see Ref.
IO-” 10-e 10-s lo-” 10-5 10-T 10-7 10-T
(9)).
Ac-
TOXIC
CHEMICAL
381
ANALYSIS
incidence. Society is divided on how it should deal with saccharin. It is voluntary, and the risk is borne by the person who perceives the benefit. Nonetheless diet sodas are culturally habit forming and society has a duty to protect members from themselves and is acting to discourage cigarette smoking. The comparatively large calculated societal impact of saccharin (460iyear) is much larger than l/50 years from use of2,4-DAA in hair dyes, so it is hard for the Food and Drug Administration to act to restrain the second use if it does not restrain the first. When replacing one chemical, known to be carcinogenic, by another it seems to me important to measure the carcinogenicity of the substitute chemical; or to put an upper limit on its carcinogenicity if the sensitivity of the study is limited. The substitution should only be made if one is reasonably sure that the risk is reduced and one is not merely jumping from the frying pan into the fire. If these calculational procedures are followed, I believe that one can have reasonable guides on whether and how to use what chemicals. In the last 2 years I
Risk/year Cosmic ray risks One transcontinental flight/year Airline pilot SO hrimonth at 35.000 ft Frequent airline passenger One summer (4 months) camping at 15.000 Living in Denver compared to New York
feet
Other radiation risks Average U.S. diagnostic medical X rays Increase in risk from living in a brick building bricks) compared to wood Natural background at see level
]O-”
(with
Eating and d.rinking One diet soda (saccharin) Average IJ.S. saccharin consumption 4 tb peanut butter/day (atlatoxin) One pint milk per day (aflatoxin) Miami or New Orleans drinking water (chloroform) 9 lb charcoal broiled steak once a week (benzopyrene) risk only: heart attack. etc. additional) Alcohol Averaged over smokers and nonsmokers Light drinker (one beer/day) Tobacco Smoker Cancer only All effects (including heart Person in room with smoker
pills regularly
FIG.
I?. Commonplace
risks
of daily
3
radioactive 3 3 , 0.. 3
I.2 \( IO ti
10 I0 3 3 5
4 x 10-T
IO
2 z. IO-” 4 ‘.: ] o-” 10-5 (cancer
3 3
disease)
Miscellaneous Taking contraceptive
Estimated uncertainty (factor of 3)
life (cancer
risks)
1.’ x 10-i’ 3 x 10-z ] O-5
3 3 IO
2 x lo-”
IO
(see Ref. (7))
382
RICHARD
WILSON
Number of fatalities (in 1975 unless stated) Mining and quarrying (accident only) Coal mining Accident (average 1970- 1974) Black lung disease (1969) Agriculture Total Tractor driver (one driver/tractor) Trade Manufacturing Service Government Transportation and utilities Airline pilot Truck driver (one driver/truck) Jet-flying consultant and professor Steel worker (accident only) (1969- 1971) Railroad worker (1974) (all accidents excluding Fire fighters (1971- 1972 average) FIG.
13. Current
occupational
risks
500
6 Y IO-’
180 1135
1.3 x lo-” 8 x 10-Z’
2100
6 x 10m4 1.3 x IO-4 6 x lo-’ 8 x lo-” 9 x 10-j 1.1 x IO-4 3.3 x lo-” 3 x IO-’ 10-4 1 o-4 2.8 x lo-” 1.3 x 10-R 8 x 10m4
I200 1500 1800 1100 1600 400
grade
crossing)
(see Refs.
(7.8.10)).
66 688
Accuracy
Risk/year
approximately
30%
have noticed a change in the public discussion of these issues, stimulated, no doubt, by the saccharin and nitrite cases. I think both regulatory agencies and the public are now willing to accept these numerical estimates, and have recognized that the search for zero risk is illusory. Finally I may seem like a fool rushing in where angels fear to tread. But the public and politicians demand answers. If experts don’t give answers the politicians will ask me. If I don’t give answers, the politicians will ask someone who knows even less. We nzusr give answers-suitably, but not too liberally, qualified with the uncertainties. ACKNOWLEDGMENTS This work has inputs from various sources; the comparisons of potency done by Dr. Edmund Crouch and Ms. Leslie Klein were funded by a grant from the Cabot Foundation with additional funding on comparison to nuclear power from the nuclear Regulatory Commission. Ms. Diane Rolinski typed innumerable manuscripts and tables from which these pages were selected.
REFERENCES 1. Federal Register 44. No. 131. p. 39.858. July 6. 1979. 2. MALTONI. C.. et cl/. (1974). “Vinyl Chloride Carcinogenesis: Current Results and Perspectives.” Ltr Medici/ie drl Ln\ww 65, 421 3. KUZMACK. A. M.. AND MCGAUGHY, R. E. (1975). Q~crrrrircrtirr Risk, A.ssc~srnenrf;w Commrrttity Erpo.rrrre to Viny/ Chloride. EPA report, December 5. 4. CROUCH. E. A. C.. AND WILSON. R. Interspecies comparison of carcinogenic potency. J. To.~ico/. Eti~~iuon. Hmlti~ 5, 1095 (1979).
TOXIC
8.
9.
IO.
ANALYSIS
383
R. J.. WATANABE, P. G.. AND PARK. C. N. (1978). Resolution ofdose-response data for chemicals requiring metabolic activation: example-vinyl chloride (Dow Chemical Company report I To.ric~~/. Appl. P hcrvmucd. 44, 58 I - 591 WILSON. R. (1978). Risks caused by low levels of pollution. rhle J. Biol. Med. 51. 37. WII SON. R. Testimony for OSHA hearing on the identification, classification. and regulation of toxic substances posing a potential occupational carcinogenic risk. U.S. Dept. of Labor April 1978. FERRIS. 13. G. (1963). N. Ehgl. J. Med. 268,430. Sowby. F. D. (1965). Hcc~lfh P/IX.\. 1 I, 879. Starr. C. ( 1969). Sc,iericc 165, 1232. Clarke, K. S. (1966). J. Amer. Mud. Assoc~. 197, 894. Sfc~ti.stic~c~/ B~~//ctrn, Metropolitan Life Insurance Co.. May 1977. National Safety Council ( 1976). Acc,idc,nr Fcrcfs. National Safety Council, Chicago. Strrtistictr/ .4hsrrrrc,r c:f’fllc U.S. ( 1976). National Safety Council ( 1976). Acc,idrrrt Fdc,f~\. Strrti.sfic~o/Ah.sfrrr~~/ c;f’tlrr U.S. (1976). Alcohol. see previous reference for details: Air travel. see previous reference for details: Air pollution. see previous reference for details: Dam failure. AYYASWAMY et (I/. (1974). UCLA report UCLAENG-7423. March. National Safety Council (1976). A~~~idt~ul Fr~r,t.s. pp. 23.87. For coal mining black lung. rail worker. steel workers, see BALDEWICZ. W.. c~f rri. (1974). UCLA-ENG-7485. November. For airline pilot. see Ref. (8). .Srrrr,,\fic~ct/ Ah.ctrtrct of the U.S., t 1976). Table 1200.
5. GEHRING.
6. 7.
CHEMICAL