F/EPA
United States
Environmental Protection
Agency-
Office of the Administrator
Science Advisory Board
Washington DC 20460
SAS-EC-88-040D
September 1DR8
Finn.' Report
REVISED 24, 1988
Appendix D:
Strategies for
Health Effects Research
Report of the Subcommittee
on Health Effects
Research Strategies Committee
-------
SOT ICE
s town sorrittan as a part of activities
of tfieScienca Advisory Board, a public advisory providing
extramural scientific information advic* to Administrator
officials of Agency.
The is structured to provide a
of scientific matters r«iat«d to facing tht* A<.j<*ney.
This for 'by Agency;
henc«i contents of this do necessarily
poiiciaa of Enviromi«nt«i Prot«ction
or of Any of
or do or
use.
-------
U.S. Environmental Protection Agency
Science Advisory Board
Research Strategies Committee
Health Effects Group
Chair
Dr. David Rail
Director
National Institute of Environmental Health Sciences
111 Alexander Drive, Bldg. 101
Research Triangle Park, NC 27709
Member
Dr. Ejla Bingham
Department o£ Environmental Health
University of Cincinnati Medical College
Kettering Laboratory
3223 Eden Avenue
Cincinnati, Ohio 45267
Dr. Bernard Goldstein
Chairman, Department of Environmental Community Medicine
UMDMJ-Robert Wood Johnson Medical
675 Lane
Piscataway, Jersey 08854-5635
Dr. David Hoel
Director, Division of Biometry and Risk.
National Institute of Environmental Health Sciences
Research Triangle Park, North Carolina 27709
Dr. Jerry Hook
Vice President, Preclinical
Smith, Kline and French Laboratory
709 Swedland
King of Prussia, PA 19406
Dr. Philip Landrigan
Director, Division of Environmental Occupational Medicine
Mt. Sinai of Medicine
1 Levy Place
New New York 10029
Dr. Donald
Director, Division of Human Risk
National Center for Toxicological
Jefferson, 72079
-------
Dr.- Frederica Perera
School of Pjblic Health
Division of Environmental Sciences
Columbia University
60 Haven Avenue
New York, New York 10032
Dr. E.Len Silberqeld
Chief, Toxics Program
Environmental Defense Fjnd
1616 P Street, N. W.
Room 150
Washington, D. C. 20036
Dr. Arthur Upton
Director, Institute o£ Environmental Medicine
New York University Medical Center
550 First Avenue
New York, New York 10016
Science Advisory Board StafC
Dr. C. Richard Cothern
Executive Secretary
Environmental Protection Agency
Science Advisory Board
401 M Street, S. W.
Washington, D. C. 20460 (AlOl)
Ms. Renee1 Butler
StaCC Secretary
Environmental Protection Agency
Science Advisory Board
401 M Street, S. W.
Washington, D. C.. 10460 (AlOl)
Ms. Mary Winston
Secretary
Environmental Protection Agency
Advisory Board
401 M Street, S. W.
Washington, D. C. 20460 (AlOl)
-------
OF THE AL AIM
Abstract
Chapter 1
Chapter 2
Chapter 3
Chapter 4
Title
Environmental Factors and Health
Kinds of long-Term Research
Research Advances in the Toxicology of
Lead
Baslc/long-Tera Research with
Application to Environmental Health
Problems
Chapter 5 Population Rtsk/Risk
Authgir
Arthyr Upton
James Pouts
Kathryn Mahaffey
Marshall
Frederlca Pereri
Wtlcox
David
Michael Ho§an
Chapter 6
-------
ABSTRACT
This to the
{both basic and applied) of EPA
1 pro¥ides a historical , the
and of of and disease,
on the underlying of toxldty with Implications for risk
and prevention, and indicates of the
Is clearly Inadequate.
2 a distinction the and applitd long-term
health effects of EPA by providing specific
Illustrate the for "generic" Issues
as well as various activities application to specific
problems and specific sittings but which be carried on a
of years, An has to explain how EPA
on baste of the by
pirticylarly as it relates to the regulatory Mission of the
In 3 the 1s as the to Illustrate
the piice of and necessity for long-sustained, basic activity 1n
the of a foundation for constructive action 1n
in health. Contlnyed
Investigations on toxldty are at one and the
the justifiable and yet of in the
field of
A of leadl activities with
potential application to environmental are 1n
4, It to highlight activities
the in this of
of the "new biology* field, as the of
and the and yse of to
and and for relating to
Other In toxicology, and
are An of
and validation. is
as a new find yseful
applications in of the Internal stryctures, states, and
of biological
Finally, In 5 the of of risks 1s
pirtlcylarly as if relates to the role of 1n the
quantification of possible risks.
inclyde of or extrapolation prlmiry
or Indirect of ind
1n and of biologically
effectlte 1n and
analysis are also the
-------
-2-
of on and within any
ire
tnd 1s as If
the EPA 1s to * policy in the
possible.
-------
-3-
1
AND
Arthur
The cerstyfy has the of which
caused the morbidity and mortality in previous generitlons. In
the of the world, the life hts
doubled, now the biblical of and
(Figures 1 and 2). This mlriculoys
to our great grandfathers, has rtsylted 1n our
of the relationship and the broadly
These advances, the resulting 1n igricylture, nutrition,
sanitation, public health, and all but 1nfectioy$
and parasitic as of in the Industrialized
world, afflictions as of 1n the
industrialized world tre 1n and
chronic and (Figure 3).
until largely as or of
aging, ire now Increasingly to Qyr
1s to the and to 14).
AMD OF
OF AN
The "environment", broa-iy, all
that act on the ind ,-Jdy. of the ire
or by himself. They and physical in
tir, food, the and the
workplace. The "eiwlfoment" 1s and changing.
Inevitably, ft a of 1n
wd mitt pie the
of 1n the of any
given may the effect of and the
conditions of
Air
of pollytion, such'as listed in
Table 1, to in and
mortality. The of ire
and may vary, on the in and
in the (4),
On at relatively in the
a variety of ire to Include
(e.g., ¥loyl chloride.
-------
,4-
radon), metals (e.g., lead, nttrcury, arsenic, nickel) and dusts (e.g.,
silica, fibers, coal) (5).
Also well are the effects of chronic to cigarette
The Incidence of lung canctr has risen precipitously, In pinllel
with the Increase in cigarette consumption (Figure 4). In
smokers, furthermore, there 1s a systematic relationship the
of inhaled and mortality lyng cancer {Ftgyrt 5), other
cancers, heurt disease, and respiratory dlseasts. • Lesser effects
tentatively attributed to passive Inhalation of cigarette in
chronically nonsnokers,
The ultimate effects of chronic low-level exposyre to otttr widely
prevalent and their derlfitlwes (such as sulfur
dioxide, nitrogen dioxide, tlpyrene, and various
participates) are less well
Although the air pollution produced as a result of conbustlon 1s a
direct cause of respiratory fatalities, 1s no of their
number; however, seven! of the of
fatalities ittrlbutable to the combustion of in electricity
(where 701 of coil occurs), (81, for
S and §00 fatalities result per 1000 Mwe of electric
yeir pollut1 on by fired plants, A
by 1n this the
and fatal 1t1«s per year per Mm of
(9,10.1, On the of a value of 7 x 10 Mm of electric
1n the U. S, by the of coal, the Imply that yp to
700,000 fatalities per year nay resylt of in the U. S,
Within the uncertainties of this 1t wtll with a
Inference by Wilson "50,000 the 2 million who die
in the may their lives by »1r pollution"
(11). One may question, therefore, the to current i1r
standards provide protection against the potential long-term
health effects of coal prodycts, which cannot be specified with
certainty on the of existing (12),
It 1s 1n the pollution
nay to health 1n the chronically
espectally children. Of Increasing concern Is the to which
elevation of the concentrations within and buildings, by
weithtr~stripping and other heat-savlnf neasyrcs, the risk of
lung 1n (13-15).
air-borne pollytints with potential health Includt
allergens of varfoys kinds. Although susceptibility to differs
widely 1nd1f1dui1s» sliable populations ire it risk (4). The full
significance of air-borne as of 1s far
established and strongly merits (4).
In the third world »1crob1il nation of drinking still
-------
-5-
s of of pollution no
on i in tht
of his in the two
of 1n the U. S.: and
(4,11). It 1s to be
polluted in i of {Figure 6), to by
metals, toxic agricultural and of
chlori'natlon or ozonization.
The of of 1n
be precisely on the of existing
is to the relationships and to clarify the
may the
(17).
is to the "you are you eat". Overall
1s Influenced by the of 1n the
diet, the of of (protein, fit,
the of the are
tht 1n of naturally
OP and the of or (18).
IB 1s the for
and tht for
life and
In tht of for to
the may tht of the 21;
tht relative of any of
to the of t of to toe
(18). In It 1s
nay art of or
the of tht net
of the may the the two of
of the to the in the of
cincer, and of In tht
world, the of strongly
As to and
at levels his to
Collectively, the of and of
my by
(5).
art significant 1n to
mty it of In
a of
is to To the
-------
-6-
of risk factors, of
1) and quantitative of
and In the 2)
surveillance and of wort-related and 3)
of clinical and laboratory for prior
to causing for Identifying high-risk and
for at ire
readily arrested, or (4).
Love Canal and Times to two of
(Tables 3 and 4), to the for of toxic
it 1s clear deficient
in many instances* the of- optimally and cost-effective
will research, as will of the
magnitude of the risks by prevailing levels of contailnjtlon around
existing sites (21-23),
The of on
alone. This be to of
Involving
liboratory and be as
1n of the of toxfcoloflcal for 1n the
7). TH1$ will to
the In of
differences and the Interactive effects of the art
characteristically it
Of FOR RISK
AW
As of the of
the of of way
differently to the total. the of a or
of vary, on the of as
well as the In
directly, act indirectly. the of
or on the of {*},
of ttt« of it is difficult or
to tht of i of Its
of of the and
of of i Is also essential in its
for on the of Its
In of the
extrapolation bt tht
of (25-26).
to tht It not bt
for of no art or
-------
to exist. Include the «ytag«nic, carcinogenic, ind of
the of Ionizing (14) and
{4). 1n this connection 1s the evidence
to life and eirly Infancy nay
impairment In the of the brain, the relationship
for which to hitherto considered nontoxlc
conceivably no £2? I.
In addition. It is not always feasible to el initiate a toxic
from the environment, the practical for mitigating Its
noxioys effects nay be to or In individuals.
For this of the of effects may be
crucial, as well as the ability to Identify Indlvldyals it early
for effective protective Intervention. for
monitoring populations, as well as for the environment,
are
Any of the of in
not the influence of and
Influtnces (28}, ts one of the
It may affect 1f not all,
inflyences, directly or Indirectly, Mortality of the
of to inversely with ind
(29). The who live In the In
of nil nutrition, ind living
conditions, to and air
pollutants, and to conditions,.
ind
which on
The of dally living in who are not
economically al so
exercise, of sleep» of
smoking, and of of ire
In {30), IE (31) and
Day {32), who
and Is in the
at large.
Also Is the of
and (331, to the
of in not to or to The
of at ill levels to
to the for to the
The -- for 300,000
per in the U. S. ind
{33) -- the of
factors, f ind In the
for or for
-------
-a-
AND OF
As environmental an
range of illnesses. They Include, for In
chronically to acid air pollution, leukemia In to
benzene, lung cancer and in Individuals to
chronic kidney diseise neurologic impairment In persons to
solvents, impairment of brain in children early 1n life
to lead, disease in indl¥iduals to and
impairment of reproductive function in men and to and
certain pesticides. Such Illnesses afflict millions of in the
United States.
environmental arise from conditions,
can be the elimination or of
exposures at the source; i.e., prevention. They are also
to prevention -- i.e., early detection in
can still be controlled or cyred; this however,
on efficiently and effectively Identifying populations at high risk.
Finally, their nay be by tertiary prevention; i.e.,
prewention of complications or disability by application of
diagnostic and at all
requires the of specific
and on the and
1n the two are to
environmentally-Induced Include, for the Mr
Act, the Safe- Drinking Act, the and
Act, and the legislation. In of legislation,
environmentally-Induced 1n society.
Given Illnesses art and highly why do
still persist! A of to situation.
1. Despite it two of regyl'atory and scientific ind
effort, relatively little 1s the
of syr^hetlc chemicals. tnd
on a of relatively as
and lead, and their Virtually no
information 1s available on tht toxldty of 80 of
the 48S000 In (Figure ?!, for
of which are closely and which
most 1s ~ -- reasonably Information on
1s available for only a of
(Flgyrt 7), twaluatiort of new 1s
inadequate,
Z. Physicians art not to tht as i of
do not of
for to
identify in origin of
are 10 of
(34K In of
origin are assigned to is age or
and for or
-------
are lost. This of Inaccyracy in diagnosis is by
the of origin are typically not
clinically or pathologically different by lifestyle
and factors.
3. Physiciins do not training 1n medicine.
Very little is In to
physicians in training to the of toxins, or to
the associations and
disease The medical receives only
foyr hoyrs of training in environmental and health dyring
the four years of school {341.
4. Persons are typically to one In the
environment and do not realize at
all. Further, the of environmental conditions
only years after onset of during this long latency
(Incubation), may may be to i
variety of environmental exposures, nay syffer various
exposures, and finally my hid
All of the difficulty and
scientists In to the of
Illness.
5. The U. S, and
art to and
conditions; Unltatlons
the of to
Inspection and ictlons.
6, unreliable and for
environmentally significant of
the of of environmentilly Illntss In our
society. As a result, the picture not an
of the of
disease.
In a lack of on the toxlclty of the
majority of chefflfcals, Insufficient and
of physiciam, and surveillance ill efforts to the
of 1rt the A
plan to the 1 lance, and of
1s
fir the detection, and of
1n is Mew York, Mew Jerstj, and California
as for an {3SJ.
OF
the It Is of the of Illness 1n the
y, S. 1s wholly or in to
Thus, if the billion In
the U. S., a 1s on ire or
-------
-10-
to (36) and are
preventable. the of be
It is
enormous.
1n the light of the of illness to tht U. S.
popylition, the on to Illness are
relatively snail. In for only of the 15,121,55?
RIO by HIH specifically to on
(37). This sum to 0.251 of the of
In the U. S, year {371. The sun for the
by ill was fir (37},
in of EPA's to the U. S.
It 1s clear the and
for the to be
The In life resylt 1n the
Influence of Defined broadly,,
§11 act on the and
Inflyences, are and in
«1r, the and the of are by man
to his
at levels, nay it
levels, t In tht
§n tht
of of In or
ifi
as of the
of any one In tht of a
be By the 1t 1s difficult to
tht to may a at
any pirticulir level. In of
of is 1s
and be on in
or
To our of tht of in
priority be to on the following:
1) and of the
21 of and
rates, to the of specific
to be to 3)
of for of to and
for identifying 4} of for
tht activity of and
it low and In 5) 1n
for particular to
and and 6)
of the of
is for 1n and In the and
of In
-------
-11-
»1goroys should be the application of existing
1) public and professional education, 2)
standards-setting, 3) of new and existing legislation, 4!
law and 5) research to evaluate the efficacy of measures.
In pursuit of Its Mission EPA in coordination with other agencies and
institutions a long-range strategy addressing of
the
-------
-12-
REFERENCES
1. Jones, H.B. A Consideration of the Aging and
Life Unfvi"rsT% of (TTTf^nTa~,"TTad1at1orr[.aboratory,~~~
~» 1955.
Fries, J.F. Aging, Mitural Death, and the of Mortality.
He* Engl and_J .Jted . 303 : 1 30- 1 35 ,
Oonabedian, A. » Axelrod, S.J. , Swearlngen, C. , and J. Mt£i_£aT_
Care _ Chart . 5th Edition. of Public Economics,
U n T ¥ e rs T ty o f Hi c h i ga n , Ann Arbor, Michigan, 1972.
Second Task Force for PI inning in
Science. Huma n__ Heaj_t h a n d _th e_ _En_v i roniB_en t - re h
U. S. Depafliiffr¥rWiTWrTa5c¥€Ton7^ni~W NIH
77-127, MiShlngton, 0. C., 19??.
Levy, B.S. and O.H. {Editors! _Qcc u pa 1 1 o n a 1 He a 1 1 h :
andPrev en t in g^ wo rtt - Re Ute d D 1 je a s e . I
1983. ~~~ ~"
6. Cairns, J- The Problen. ScU^Amer. ^33:64-78, 1975,
?, Doll, R. An Ep1de«lQlG§1ca! of the of
8. H. of EnyP^gctlon, .
~~~'
9. Morgan, M.6. , Norrls, S.C. , Htnrlon, M. , , D.A.L. » tnd Rlsh, W.R.
Technical 1n Policy - A Sulfur Air
Pollution ^:201-Zli,
10. Morgan, M.G. , Henri on, H. , Morris, S.C. , and , D.A.L. uncertainty
in Risk Enyr1 ron ._^ Sc 1 . _ Tech no 1 . 19: , 1985,
11. to the Editor. Public
238:10-11,
12. Ttsk on and and
Cancer and and Lung P*_seasg,__3rdi to
C~TivTroSienlaT^ Igency7~~ [[[ ' ............................... ..... ~ ....... ~
D. C. ,
13. on Pollutants. Indoor .PoVlutants^.
of o. c. , iwn
14. on the Blologlctl of
-------
-13-
15. Council on and Evaluation
of Occupational and Environmental to and Rtdort"™^
on~Ra^TIfTonnjro^eTtfoirTf»3~Heasupements ,
Washington. 0. C, , 1§84.
18, Dlckson, 0, Toxic on
Clean Up.. H:46-5°i 1982*
17. on Drinking Drinking and Vol. 4.
National of Sciences, ~~~~~^
18, on Diet, Nutrition, and Cancer, Dl^et,- Nutrition, and Cancer.
National of OTTT
19, Doll, R, The Epidemiology of Cancer, In: 1n Cancer
jyT^^
Philadelphia, 1979, pp. 103-121.
20. Wiiss, 8. and Clarkson, T, Toxic and the
Implications of for Technology Transfer. jjjTban
6£:216-24Q,
21. Office of Tectin§1ogy
U, S. CoigressTwil^
22. Materials
of
TJasRTrTgton, 0. C. , Ii83.
23. §n to
of Mul Contaml of
24. Nation*! of - Council, Tox1c1ty
NaWoniT"
25, on
~™^^
26. i.S. to
Teratogentsfs, Effects. j._^er.CoTJj_Tox1_coV._
^;113-123S
27. Bellinger, 0. , Levlton, A., C. » H. , and
H. of and
and Early N, Engl . J.
316:1037-1043,
-------
-14-
28. H. §fw™!!t^^
29. Mortality: and Wales, 1970-1972.
1978.
30. Belloc, N.B. Relationship of Practices and Mortality, Prev.
Med. 2_:67-81( 1973. ~^
31. Lyon, J.L. J.W., and West, D.U, in
and non-Momons In During 1967-1975. J-Nat-Caricer
Inist. 6:10SS-]Qi2, — __ _
32, Phillips, R.L. , Garfinkel, L, » J.M. , M.L.,
Lotz, T, , and Brin, B, Mortality California
for Sites. J. Mat1.Cjncerlnst.
65_:1097-1108,
33, General, ^okjjiqajidjjealth. of Health, Education,
ind ............ IT. ........ T. ....... , ........... TfTf .
34. Levy, 8.S. The of Health 1n United
fl¥e-Year Follow-Up of An Initial Survey.
:79-80' ~™~
35. S.B. and P.J. 1n Mw
of °~~~~~~~~ "
36. of
___ .
37. national Institutes of Health. U, S. Printing Office,
Washington, 0. C. ,
-------
-15-
1. Atr Pollution
of
P1ace
Valley, 63
Oonora, Pennsylvania 20
London,
Mew York, Mew 200
London, England 700
-------
-IS-
2. In May of
1, By providing of §r
-- of
-- of or
or
-- Products of
-- of
residues)
2. By affecting of
— Pro¥lsf§n of for of
(secondary amines, nitrates, nitrites)
Inhibition of of as tn
(Vitamin C)
-- Alteration of of bile and
(
— Alteration of of
by fat, In
-- of
-- Affect on of (fits,
3. By of
— (alcohol,
-- on In (fiber)
Inhibition of A,
191
-------
-17-
3. Pollution
P8B« St. Louis, 1973
Lead 1976
Italy 1976
California 1977
Love Cinal, Mew York 1978
Oioxin
Oioxin New
aPC8 as P88 a$
bfphenyls, as and it
1
-------
•18-
Table 4. Examples of Outbreaks of Mass Human Poisoning From
Toxic Chemicals
Date
Location
1930
1934
1952
1952
1952
!955
1956
1958
1959
1960
1964
1967
1§68
1971
1976
1981
1984
U.S.A.
Detroit
London
Japan
Morloga (Japan)
(Japan)
Turkey
Kerala ( India)
Morocco
Iraq
(Japan)
Qatar
Japan
Iraq
Pakistan
Spain
BNopal
TrJorthocresyl
Lead
A1r pollutants
Parathlon
Arsenic
Methylmercury
Hexachl
Parathlon
Tr1 orthocresyl
Ethyl mercury
Methyl mercury
Endffn
Polychlorlnated bfpttinyls
Malathlon
Toxic oil
01
Mo_._A£fecte_d
18,000
4,000
4,000
1 ,800
12,159°
1,000
4,000
828
10,000
1,022
646
691
1.665
50,000
12.SM
2»000C
of
Thest tht of It was
that and 131 died.
C0eaths« Ttte full of lingering and
unknown.
(Froii 20)
-------
-19-
m 40 so
OF
ao
figyre 1
1n and
1).
-------
-20-
100
2
The Survival In the
U.S. 80 of the
the 1900 and the
hid
by 1$ n§w the
of in 11ft. 2).
-------
-21-
fff all
1
flf fttHJ
221
AN
Of P"^™^^
* Mrty C
of
c
— MIIUU>
^^
3
a
a -
3
a
3
of 1rt the !S67»
as 3).
-------
-22-
in ind
1n ind
61.
-------
-23-
for «§•
mm
2M
tm
t
t
t
I
» at
^^^^^^^^S iBUPii • Sit 1
4t
Figyre 5
of In
In to of
Per Day. 71.
-------
,24-
= pollution
- may not be but the 1s
not
0
metals, is zinc, and
i
development
* tnd
and indystrlal
Figure 6
(As by
U, S. 161
-------
-25-
:=>V
t»f
«MI
M
A
II I* 1 M tl
I U 4 J*
14 U
II
u
1
*
=
line » toxlclty
»
)
- No
of on of Different
for
241.
-------
-26-
Chipter 2
Of LONG-TERM
Foots
LONG-TERM HEALTH EFFECTS SUPPORTIVE OF EPA
I. Basic Research
Bask research in EPA programs nay or nay not be directed
spedficalif at support of certain applied research programs. Such basic
research miy seek, only to understand detptr levels of the general universe
of problems attacked in the specific, discrete long-tern, applied
researches {such as described just below). The general basic research
philosophy 1s that undtrstandlng the chtuticali
disease can lead to earlier detection or better for health
effects (and better designs of epidemiology studies), analytical
» etc. All of this can and often lead to for
regulation and, thus, regulation. Section 111 below)
of this basic research cm be it using of the
"new biology" to our ability to or to
identify and quantify specific effects of tor had actors In)
nlxturts of chenricals occurring "naturally". Ov«n11 the "
distinguishing of b«s1c 1s 1t
"generic" Issues, ind 1t not necessarily be any on« specific
nor "qylcfc* A$ 1t be for
seven! years to be effective and to glvt tht kinds of findings will
be uscfyl to "applied" It 1s, true
that often the useful ftcts and new in resolving tny
environmental turning to laboratories
basic research.
There art of the kind of
(and 1$ risky) any of the of
night be;
A. New to ind quantify dioxlns
lisle his Identified characterized in
intracellular "receptor" for 41oxin$ tn^ related
curled out rtsylted 1n tht partial purification of this
receptor, ami of the ind specificity of
severil of ttw b1§1o§1ci1 of d1on1ns. Recently, the "ntw
biolofy* ttchn1fu«»s this "dloxin* rectptor his clontd and now be
available to (and In
his to one posslblt application of
use of this to tnd
of it lt«tt d1ox1n»Uke 1n
wlxtures—ptrtlcularly of the dloxlns 1n soils,
Ttii on tht *i1ox1n* 1s tut kind of
effort «iy now to "fruition" (e.g.. 1n tt« nw
-------
-27-
for dloEfns In mixtures). 3ut it his over years,
and to the practical/applied of
Gbjectlrts, hts not of to of the EPA
B, New for detecting to toxic
chenical s
The are a of steroid. 11p1d,
and xtnobiotic mftabolizing 1n a wiriety of living
(from yeast to . over at least 35
his led to of the diversity and of
in The "new biology" his given y$ new
tools for qyantlfylng and Identifying of It is now
possible to "fingerprint" the an^ of
of P-4SO in of (Including and plants,
research his described 1n detail of P-450s to
various '(including all
long-continuing, bislc be
giving us for looking it the of plants, animals, and
to chemicals--e.g., the and of P-450s
to reflect to things like
Fyrthtr, basic ! ly 1n nay give
ys a for and
(of to
for flc P-45Qs.
II.
irt of activity
to and but be
on a of can be 3
U ind
pirts/step$--whert one usually be be
initiated/planned, 2J a but
pirts of can be on 3)
and validation.
A. 1n
This 1s a of
of in projects--either In
their §r ire but the key
1n Is 1s i
and up the
1, The layer and
Is i his for
Tht ind of ire
of tht
1n U¥ in^
on nay be
-------
-28-
1 1fe- threaten! ng, direct. in this
overall
i. The first at the Issue— Is any
evidence we ire actually losing The to
this {data supporting this) 1s still and (at
in quarters), but the first indications that to
a loss; therefore., 2
b. The to be: be
this loss of Is any contribution (e.g., chetical)
can destroy and is likely to get to the layer!
about the chemistry md Interactions of light, *nd had
to be first. arc still out
at this
c. The was to gather the
of materials/chemical s (e.g., 1n
the liyers of the New for
collection of etc. to be developed, validated and
d. real-life of had to
be and for their contributions to the
problem.
i, as to bt
in the of it the had to
be
Thus, of
here-— chemistry,
sociological/psychological , §nd political. the to be
In the overall of dealing on the
of just and on of preceding,
2, He and of rain
A of but ill
or of pollutlon has the
effects, and really r§1n 1s to be
primarily Industrial art
ind of One In
Is the to flora, and 1n
1s due to and or
1s by cars/traffic, A of has
and art continuing. It fs of
the the Is "yes" to
effects/hunm rain and car
This i of and
out One of the on all
f Including of of
1s the
In if
at an it
-------
-29-
1n 1987. The of this will be in |nv1rogient_i1_
HtiUh Perspectives 1n This effort In bo theology""and '
TuMarTheTrtrriFfeTts of rain his on for years/decades, and
ire only now barely visible.
B. Long-term studies with concyrrent
arc Just a time—the
are the study just can't be in short
"pyrely" epidemiology fall hire—where the
effects of low level, chronic or to
resolting only years after exposure or In populations that "age" to
effects. Most studies on possible of cancer or on
carcinogenic of chemicals art So are i¥a1uit1ons of the
of other slowly developing effects/diseases (e.g.,
kidney failures, liver and CVS or CMS effects). evaluations.
involve multiple at the but continuing for a long
on the populations. Chronic toxldty In animals Are a
of this kind of There are
i. The "Six dttes of of air
pollution—comparing various indices of 1n H¥in§ in 6
cities of widely ¥iry1ng of pollution. This has
on for now, part of the Increasing clarity In this
resylts from now 10 years, but
1s the of new and analysis to the for
effects. The point 1s this
of the populations/regions years to
and to clearly the In
air pollution fwhlch the of the in 6
"regions". The principal effects now are on the
(lyng fynctlon but ft.g. „ kidney, C¥S) my be
to be as studies continue.
2. The effects of polychlorinated biphenyl (PC8)
on childhood This with
in the U.S. and (e.g., oil 1n and
Japan ind Hke the of oil with PCBs
along highways, and the of living near, or walking along
highways). From short- and 1t was
of PCBs not acytely but
in and sybtle. Therefore,
to follow {for 1n of
and especially in any children The
of levels of to on childhood
ire now In only
dentally-exposed populations and a large of "Itss-txposed* and
"nomaF/unexposed and children for
3. The of
Again, an accident—the of and
the of this and of
the 1n are still
-------
for effects, again,
are and subtle.
C. and validation of
In the for detecting and quantifying new
environmental toxins/problem do not it the
"problem" ire first discovered. This set of "long-tern"
activities Is vital in any to and affect
environmental hazards, are but only a few
be given;
1. Dioxins fPCODs) and (PCDFs)
for ind
quantifying "families" of did not the
first "poisoning" in The of
materials 1n Is small, and yet» in
animals, chemicals toxic effects at low
concentrations. We are only now the to
quantify and selectively identify and the of
chemicals found 1n real life of the In
analytical to this of
The of and analytical to
Identify the dlbenzofyrans is of the and dloxln
and also as contributors to of the toxfcologlcal
This his
it and 1s not yet. Validation of all
1s still occurring.
Z. Lead
W1th/1n we
of the toxic 1n "deep" tlssyes. at
without painful or the yse of 1$ a If
the of 1nfomat1on *e are to be generated—particularly for
long-term stydies, or for chronic {although this
infomitlon miy be vital for
metals, to only briefly in tissues
and flyids. of and In relatively
like (or fat, etc,), to
of are
Non>1rwas1ve §re especially useful/attractive for
for In the of
lead be now X-ray flioroscopy. Validation of this
1s now taking place—total to use will be
-------
-31-
ten years 1 f all well — a long-tem effort typical of several
others.
III. How EPA on by
Federal Agencies
Health within the EPA Is ultimately directed the
regulatory mission of the Agency, While 1s often of an
"applied" and/or "immediate" which specific
the with in an manner, or
fundamental research is the only of Improving the scientific
rationale underlying regulatory decisions. It is vital the EPA
scientific staff maintain current of re1e¥tnt by
performing research within the Health Effects Laboratory and
by closely following the latest 1n toxicologies!
The effectively Its mission without
scientists 1n of tools of basic
research. Without this and health scientists within
the Agency would be unablt to effectiwely translate the findings of
fundamental into the sypportive of the
Agency's regulatory mission. by
EPA represents only a fraction of which 1s to
its regulatory mission, the rely heavily on
information by Federal particularly by the various
Institutes of the of Health and Services, These
organizations for of the scientific
In biology, and
research that have of for
monitoring, dosimetry, to*1colog1cal testing, and
Basic at the
national Institutes of Health has substantially the Agency's
regulatory and policies. on the of
mutation, xenobiotlc metabolism, pnarmacoklnetlcs, and moltcular
performed at the Institute of Environmental has
applications it EPA In and
metabolic activation for Iji vitro
for ng, for
biochemical epidemlilogj. by the
Institute on of cardnogenesls and survelllanct has
contributed directly to the of toxtcologlcal and
gyidelints for by the EPA Office of
Health and EPA 1s directly
widtly and in the of neurotoxlcology.
The discovery of cell within
the their differential
vulnerability! is Itadlng to in of of
neyrotoxiclty and for the of
neyrotoxicologic will to
future guldtllnes for neurotoxiclty testing.
In addition to the yse which the of basic
information by indirect
-------
-32-
(infomation 1n the literature and discussed at scientific
forums), the also active collaborations which
of findings and/or expertise.
EPft scientists frequently in collaborative studies with
scientists in as well as their colleagyes in
who nay be by agencies. These research efforts often
of expertise in new technologies and new findings that may
applications to the regulatory mission of the Agency. As an example,
research on mechanisms involved in the successful fertilization of the
oocyte has led to int.^ragency collaborative to improve for
the evaluation of maie fertility. Other efforts delineating the
fyndamental factors involved in absorption led to joint
interagency projects on the of
methodologies for the of the kinetics of exposure.
Clearly, it woyld be possible to this list of relevant
since mych of the scientific information utilized by the
for regulatory decision-making guidelines fomylatfon rests on a
foundation of basic research.
-------
-33-
Chapter 3
IN THE OF LEAD
Kathryn
PREAMBLE
The place of and for long-systained basic research activity
In the of a foundation for constructive action in important
problems in environmental health coyld be Illustrated by reference to any
of several current He the and
its dangers or toxlclty to this purpose. as § public health
problem has for Iff not centuries). Yet howt what,
and to do Its effects and
treating not have only recently, and only as a
result of long-continuing research. For one thing, only long-range,
nwltidisciplinary, continuing basic has giwen us the varied tools
we to of the subtle (yet important! effects
of lead. We counting to worrying things
like behavior and tn children—but only
we now for of lead. This 1s
the story of an health only
slow-n»v1ng to explain]
and by far-sighted who long-ringe
was and would to be cost-benefit
Background
Understanding the of by
exposure has 1n this centyry. Into the toxic
effects of a his the discipline
of clinical and toxicology for the five
Fundamental mul ^disciplinary laboratory 1n as
biochemistry ana'physiology his a najor key to this progress,
has long to be acutely toxic at
exposure. In addition, *e OB 1n tht
1970*s and two of
of on it
levels ont of the of the
on tht
Is in of
cularly
In children, to lead, as 1ngest1on
of paint, his to a
characterized by convulsions, and 1n In
with to lead, a
"wrist and drop," and art the
conseqyences.
-------
-34-
The challenge has tc ".arstand that the of health
by lead was e-.rns1ve the clinically-obvious
has this challengi esisdally difficult Is
lead pollution has at lewels, an
byrden of 1n a sizable portion of the popylatlon. During the 1970's
In metropolitan areas, young children frequently Nad
concentrations greater than 40 g/dl; a concentration associated with
several neuropsychologlcal The Is to the
etiology and severity of health are so are
considerad "normal." Irs the of public and
medicine mortality iftd morbidity (i.e.,
reports) to understanding the This reflects
and has been possible only of lonf-ranfe support of enflronnentil
research.
exciting recent findings with to understtndlng
of the toxicology of is the realization 1s of
producing toxic effects in adults and children at relatively low levels of
I.e., levels that ire insufficient clinical
Only a igo of
"sife*. 1s now to a of •
toxldty.
h«$ of
Is a Involving Th«
red cells, the and -the are the
In
In early IfOO's so
routinely for
(1935) the of to
poisoning for the and 1133 wts
in of 3400. The of children* nho art
sysceptible to the of In
the 194.0's the 1%0's of of
the the Prior to the of
hi4 «
rate of §51
of poisoning 1s the
predominant, :*For and (1143) and
clinicians of
poisoning
sensory deficits, and bthavloral dysfunctions. Ptrlsteln and
(1966) 1n 371 of who
poisoning withoyt of cncephiloptthy,
Through to identify
and to
of to clinical of
toxicity a control;
not clinical of
intoxication, identified «h!ch ire it
-------
-35-
hlgh-dose exposures. The limited reversibility or 1r reversibility his
documented fn many of the clinically-reported, neurologic effects. Using
these clinical studies as a gylde, long-range, multi disciplinary reseirch
has extended the understanding of lead toxicity .to the cyrrent emphasis on
btomarkers of exposure, dose- response relationships for specific effects,
and identification of sysceptible subgroups for these effects,
ResearchF ind i n gThe9 7 0*sinM9B(rs
The general picture of adylt and pediatrlc lead poisoning has changed
in recent decades. The overall pattern is Identification of significant
adverse health effects at progressively lower exposures. These can be
arbitrarily separated Into neyrobehifloril , hematopoletlc, renil /endocrine,
and reproductive effects. As a part of this effort, differential
sensitivity of various sybpopylatlons has revealed. Identification of
effects occurring at environmental exposyres considered "normal1* has
coincided with redycing environmental exposures 'to lead. Only through
reduced exposures can the resylts given by toxicology and epidemiology
research be evaluated in general hyraan populations.
I. Neyrobehavloral Effects
Recognition that neurobehavloral effects in children are produced
by lead exposures considered "normal" 1n eirlitr (e.g., blood lead
concentrations of 20-50 g/dl ) has tht significant
findings in the 1970' s and s. Long1tud1nil studies during the
10-15 years built ypon early and cross-sectional studies. The
longitudinal prospective designs hate permitted gathering liproved
information on exposure histories. Information on exposyre levels and
patterns is clearly important 1n assessing effects of a cynulitlve toxicant
on endpoints such as neyrobehavlonl function that nay reflect changes
induced at far earlier, but critical, periods.
The most consistent finding of the prospective studies is that an
association exists between low- level lead exposures during developmental
periods (especially prenatal ly) ind later deficits 1n neurobehavloral
ptrformance. This latter 1s reflected by Indices is the Bay ley Mental
Development Index, a well-standardized for Infant Intelligence, Blood
Itad concentrations of 10- IS g/dl constitute a level of concern for
effects (EPA, 1986). In addition, Impaired neyrophyslologlcal function has
issociated with Increasing blood concentritions children.
These functional deficits Include changes 1n the auditory brainstem evoked
potentials and evidence of lead-related hearing acuity {Robinson et
al.t 1985, 1987), 'These subcHnlcal toxic effects of on the central
nervous system are generally considered to be peminent and Irreversible,
and they are associated with permanent loss of Intelligence ind
irreversible alteration 1n patterns of behavior.
Belli et il (1987) significantly
on tht of tn
uppcr-«1ddlt class Itad Itvels 1n the
of 10-25 g/dl, adult
It veil 10 ind 12 g/dl on ttit 11
-------
-36-
for ttw tt i1f It
be art
one of the
of the In tht II
The is by
Typically, adults ire likely to
nervous effects. In the early 1980's investigators to call
to "subcllnlcal" by in
velocity in lead not neurological
involvement et al., 1165). In the 197Q*s et al. 11972,
1975} the slowing of the velocity of the
and ylnar md 1n
70 g/dl.
Investigations of the of an
threshold, coordination, and physiological
and psychological 1n with blood below'
80 g/dl et al., 19751,
II,
his i of clinical poisoning in
children and adults. of
1s now to In
children at of 30 g/dl. of
and the of it i of In
the red cells the
to of 1n
children. The for In 1s with a
of 15-18 tt al.,
1n to
The accumulation of IX as or
as protoporphfrirt in Is not only in of
but signals Injury, The final
of In the injyry to the
mitochondria can a of subcellylar
and Implications of
include; of to all cellylar
of calcium
metabolism; In control;
detoxification of and of
(e.g., of
111.
1n children a
with glucosurfa, and to
of the to in
has tnd
in adults. adults, in for
all ill (specifically, of the
liver, and lungsj, nephritis, ind
(I.e., dye to not
-------
-37-
in a longitydlnal of in battery
plants tnd lead (Cooper, 1985}.
A statistically-significant his
In systolic tnd and in
old, the 11
populitlon (Plrkle et *1,
Impairment of the endocrine functions of the kidney
reported to occur at of
effects required development of several of research;
A. Understanding the metabolic activation of Vitamin D to
1,25-dihydroxyv1tam1n 0. This metabolite is critical to regulation of
calcium Ism.
B. Recognition that"lead Impairs various 1n
biosynthesis and function of 1,25-diHydroxy¥ttam1n 0.
Currently, the studied at
is the tubule of the kidney.
25-hydfQKjf¥itimin 0, 1n liver 0, a
hydroxylation Is by the 1, ,2S-hydroxy¥lt«ft1n D
hydroxylase. in vitro (following In vivo
of to 1 iTEsTfhi
activity of this Findings a clinical Investigation
children 1 D lt¥els
in to to
of Itad, 1n of
1,25-d1hydroxy¥itaffl1n 0 yp to levels similar to 1n children
serving as controls et al., 19801.
has 1,25-d1hydroxy¥lta«1n 0
with i of
concentritions, 12 to 120 et al., 1982b).
IV.
Early 1n the a of of on
with
included still-birth
rite, and a higher, and early childhood mortality
children of
high, I§ng1tyd1nal,
to of lead,
important on effects at the of
levels. et al. (1986) the of
deliveries the 37th of significantly
to at delivery,
excluded, the of the The of
deli¥ery a* levels In
of 14 j/dl or MIS 8.7 the it
yp to 8 g/dl. 1n age at
by et §1, (1986),
et al. I1984J, et §1. (1982), and tt al. I1987a,
-------
-38-
b). The from Indicate for 10 g/dl 1n
58 and 601
on the age of the
The of et al. in
in miscarriages and still births In the high-lead In
contrast, this
concentration was lower for still births for 11 we births.
to an
1n the of it low 1s of
for the fields of and public health. Until
recently, of 25 g/dl and
and only five ago the for (CDC)
25 a level of
in children. on the basis of
it 1s In children at
levels this guideline. Thus, the toxlclty of
lead it low is to § re-evalyatlon of
for the of to
The of the
tnat in the
the and
Survty In 9.11 of all
children In the - 1,5 million - hid
of 25 or tt al., 1982a).
children the of (high
wi$
findings on the of
(high blood In the
or» subcllnlcal toxlclty, a of chill ing significance.
findings 9% of ill in nation, and 251 of
minority children, may be suffering irreversible neurologic, Intellectyal ,
and ts the result of chronic, to
lead. The impl Nations of for public and
environmental ire
This has a one of the
and It 1s t
eontinyes the findings ind implications. It will
only 1f the of
us to are ind
research Invtstigitlons on toxlclty art it one and the
the justifiable and of
activities In the entire field of So
has 1n In no it
of all the his
tet His 1n has off
and Is still It Is "apology" for
we can for the field of
health science, may be the specific of of
for any one
-------
-39-
REFERENCES
1. Bellinger D.C,, Neddlewan H.L, Leviton A., Waternayx C., iablnowltz
H.B., Nichols M.L. (1984). Early Sensory-Motor Development and
Prenatal Exposure to Lead. Neurobehav Toxlcol Teritol 6:387-402.
2, Bellinger D.C., Leviton A., Witernaux C,, Neddleman H.L., Rabinowltz
M.8. (19875, Longitudinal Analyses of Prenatal and Postnatal Lead
Exposure and Early Cognitive Development. New England Journal of
Medicine 316:1037-1043.
3. Bornschein R.L., Syccop P.A., Dietrich K.N. , Krafft K., Sroti J.,
Mitchell T. , Berger 0., P. B. (1987a). Prenatal-Lead Exposure
and Pregnancy Outcomes in the Cincinnati Lead Study. In: Linberg
S.E., Hutchinson T.C., eds. Internationil Conference: Heavy Metals in
the Environment, V 1: September; New Origins, LA: Edinburgh, United
Kingdom: CEP Consultants, Ltd., pp. 156-158.
4, BornscNein R.L., Grote J, , Mitchell T.. Succop L., Shukli R. (1987b).
Effects of Prenatal and Postnatal Lead Exposure -on Fetal Maturation
and Postnatal Growth. In:'Smith M., Grant L.D., A., eds. Lead
Exposure and Child Development; An International
Lancaster, United Kingdom: KTP Press.
5, Byers R.K., Lord E.E. (1943). Effects of Poisoning on •
Mental Development. Am J 01s Child 66:471-483.'
6. Cooper W.C., Hong 0., Khelfets L. 119851. Mortality 1n of
Lead Battery Plants and Lead Prodyctlon Plants, 1947-1980, Sctnd J
Environ Health 11:331-345.
7. Dietrich K.M., Krafft K.M., Bier M., P.A., Berger 0.,
Bornschein R.L. (1986). Early Effects of Fetil Exposure:
Neurobehavioral Findings at 6 'Months. Int J. Biosoc. Res. 8:151-168,
8. U. S. Environmental Protection (1986). A1r Quality Criteria
for Leid. Research "Mingle Park, NC: Office of Health and
Environmental As$issa«nt,t Envlronnental Criteria ind
Office: EPA No, EPA-iOO/8-83/02iif-df, 4», Availible from:
MTIS, Springfield, VA: PB87-142378,
9. Hoffman F.L. (1935). Liad Poisoning Statistics for 1933, Am J Public
Health 25(2; 1190-100.
10, Mahaffty K.R.» Annest J.L. , J., Murphy R.S, (1982a). «§t1ona1
Estlmetes of Levels. United States, 1978-1980. New
Engl J Med 307:573-579.
11. Mahaffey K.R. , J.F. , R.W., Peeler J.T., c.M.,
H.F. U992b). Association-Between
Concentration and 1,25-d1hydroxycholeco1c1ferol Ltvels 1n
Children, to J CHn Nytr 35:1327-1331.
-------
-40-
12. A,J., Vlipani G.V., E.F,» P.A., Clark
P.O. 11986). The Port Plrle Cohort and
J Epidemiology 40:18-25,
13. M.R. , A.t S.J. , A,, I.M..
Maconesplc H., R. , Low A, {19821, of and
Infant Exposure In Glasgow. Med J 27:113-122,
14. National Council (1972). Airborne in Perspective.
Washington, O.C. on Medical and Biological Effects of
Atmospheric Pollutants,
15. Perlstfiln M.A., i, (1966). of In
Children. Clin
16. PlomelH S., C.» Zyllow D,, Curnn A.. B. {1982}.
Threshold for to Synthesis 1n Children, Proc
Natl Sci USA 79;3335-333i.
17. fHrkle J.L., J.t Landis J.i., and W.R. Thi
Relationship Ltvels and and Its
Cirdiovascyltr Risk Implications. Aw Jr of 121:246-258,
18. J.D., B.B., Nicholson J. (1975). of
to y. S. of Health,
and Welfare. for and
0, C.
19. G. , S., D., C.t S. i.,
P.» O.A. (1985). Effects of Low to
on Auditory Potentials 1n Children,
WHO Office for pp. 177-182.
3).
20. G.S., R.H. , R.L., O.A, (1987).
of Environmental on the as
by tnt and
In Children, In: S.E.,
T.C., in the Environment,
VI: New Orleans, LA: CEP
Ltd., pp. 223-225.
21. J.F., R.y., A., H.F.. K.R.
(1980). In 1,25-dlhdroxyvltatftlri D In Children
Lead New Enfl J Wed 302:1128-1131.
22. A.M., S. (1972). for
Sybcl1r»1cal ir J Ind ted
23. A.M., Tola S.» S., S, (1975). Subcllnlcal
it "Sift" of Environ
30:180-183.
-------
-41-
24. T., Ferrari E., Colucci d'A.C. (1965). Velocita de Conduzione
Net Satyrnlni. Folia Med. (Napoli)
-------
-42-
4
WITH
TO
PREAMBLE
In this a of of the
basic/long-term applications to
environmental (especially 1n humans). This not
the of
will or be of to It Is,
, however, in at carefyl choices of studies which
for the of this their
applications could on health. As
then, this is a look at the and of
has 1n the
-------
-43-
Of BY
INTRODUCTION
are cellular are
and initially as
the transduced of trinsfoming retrovirysts (1).
studies can be to
causing by of retrovlril
involvenent (2-4). Include or DMA
as or amplifications. The
actlvition of by 1n
levels of expression of protein product, or 1n or
levels of of in protein,
Of
The activation of In and
and 1n has 1n
the In for
Imply of are by
and this is in fri
Induction (5-6K -Alternatively, of and
is 1n
(7-9), The of bt 1n
the of 1s at The
low of at two r«s and «re for
the of celTTTji (10),
in to the of the of
specific is be t
1n (ID, The of
1n win bt 1n of
of to
The of rt$ to one 1n
the nwltistep ~of~carc1nogenes1s for a variety of and
(5,61, The activation of by point 1s an
early 1n and may be the "Initiation" 1n
Thus, a by of ras_
cm potentially §ne of the
1n to the cNeufcal. Is this to
classify the as a
rajj In
{6}. The of !n
the of Is uncltir at is will as
the non-jras 1n can be by or
radiat1on~T6K
-------
-44-
are classified as potentially hazardous to on the
basis of long-term caret s stydies In rodents. While rodent
tarcinogenesis stydies are often designed to tninic the route of
exposure in environment or workplace, the of a given chemical is
usually higher than that which actually occurs in human exposure. Coupled.
with the appearance of species- and strain-specific spontaneously occurring
in vehicle-treated rodents, this complicates the extrapolation of
rodent carcinogenic to risk. analysis of tymors from
spontaneous origin and from long-term carcinogenesis studies should help
the mechanisms of formation at a molecular level. For
instance, the finding of actiwating mutations in different of the
H-ras_ in furan-induced liver versus finding activating
mutations in only one of the H-ras in Hver
that the chemical Itself activated the H-ras proto-oncogine by a
genotoxic event (12). In general, comparison of patterns of
activation in spontaneous versus chemically-induced rodent tumor?,
with cytotoxic information, should be helpful In determining the
chemical in question is nutageniCj cytotoxic, has a receptor
of promotion, or combination of (and of
action. This type of anilysls might be of particular Importance for
such as furan furfural 112,13) which negative for
rnytagenlcity in short-term bioassays.
APPLICATION TO OF
Another which should be helpful 1n species-to-species
extrapolation of risk from carcinogenic is to examine oncogens
activation and expression in tymors from different by the
agent. For example, K-ras with the activating lesion In
12 were In boWrat §nd Induced by
titranttromethane {14}. Even little 1s the ONA
properties of this , this is
acting in the to 1rt nts and mice.
The role of chemicals and radiation in the activation of by
amplification, translocatlon, and other sis which
can alter expression, is currently Investigated by
groups. Also, as life increases, it to
chemical-Induced of the progression of to
malignant These and similar to explore the
by which in may of
the uncertainty In risk analysis of carcinogenic
-------
-45-
REFEREMCES
1. JM. Viral Cell; 42:23-38.
2. Varmus HE. 1984. The Molecular Genetics of Cellular
Annual Rev _18:553-612.
3, Weinberg RA, 1985, The Action of in the Cytoplasm and
Nucleus. Science; 23Q;?7Q-77i,
4. Bishop JM. 1987. The Moleuclar Genetics of Cancer,
Science; 235:305-311.
5, Baroacid M. 1987, las Ann Rev of 56, in press.
6, M, Reynolds S. Activation of by Chemical
Carcinogens in: The Pathology of Neoplasia. A Sirica, ed, Plenum
Press, N.Y., N.Y. {In 1988J.
7. GM, 1C, M, HE, JM.
Amplification of i-myc in Correlated with
Science 224:1121-1124.
8. RC, GM, Sather H, Dal ton A, SE, KY,
D, 1985, Association of Multiple of the
With Progression of Neuroblasts, The New
Journal of 313:1111-1116.
9. OJ» Clark GM, SG» Levin WJ, Ullrich A, HL. 198?,
Breast Cancer; Correlition of Relapse and Survival With
Amplification of the 235:117-182.
10. Land H, Parada IF, Weinberg RA. 1983. Tuntorigenie Conversion of
Primary Embryoflbroblasts Reqyires at Two Cooperating
Nature (London) 304:596-602.
11. Barrett JC, M, Koi M, 198?. Role of and Tymor
Sypressant 1n a Multistep of Cardnogenesls, In:
Syraposiyin on fundanental Cancer Research. Volume 38 (F. Becker,
ed.,), in press.
12. SH, Stovers SJ, Patterson R, RR, SA,
MM. 1987, in B6C371 Liver
Tymors: Implications for Risk 237:1309-1316.
13. Tennant RW, Margolin BH, Shelby MD, Zeiger E, JK, Spalding J,
Caspary W, Resnick M, Stasiewica S, B, Minor R. 1987.
Prediction of Carcinogenicity in fran ln_ Vjj£0
Toxicity Assays, 236:933-941.
14. SJ, Glover PL, LR, RR, SH,
MW. 1987. Activation of the K-ris 1n Kit and
Lung Tynors Inductd by Chronic to Tetranitrotftethane,
Res 47:3212-3219.
-------
-46-
AMD
Fredertct P.
INTRODUCTION
in in molecylir biology and biochemistry
the of to of
to carcinogens. highly
techniques can and the internal of
carcinogens (the of the carcinogen or Its ieTaSoWtFTFF
and fluids) or the b1_oT£g1cainy_ effect 1ve_ {the has
with eel TlTTaTiSaTn^TeTilTCrTucTrTs ON A, IN* or protein) in
or a This of could be
especially valuable in of etiology by providing a
mechanistically relevant link on the one
and clinical on the molecular
in and the potential to
of risk in to of a
carcinogenic to applications of "adduces
research" could directly at EPA for
of and risk to
Various are available to Ch«i1c4l-8pec1f1c lesions
(such as for ONA and as well as
specific biologic alterations (such is or cell
mutations). -Table 1 jives of currently available for
the biologically of As c§n readily
be all pertain to
genetic toxlclty. Moreover, all available on readily
es for the itself, limitations,
biological significant potential In etiology
and risk
-------
-47-
Tabl« 1. of Biologic Methods
End Point F1jd
Biologically affective
ing, fluor- HBC
Spectrottetry
(protein) RBC
analysis, HPLC, gas
chroma togriphy
Excised HPLC,
UDS Oil cylture, • WBC
SCE WBC
Mcronyclil
WEC
rations
cell Autorid1o§riphyf light MBC
Somatic, cell RBC
tglycophorin A)
quality Analyses of count, motlHty
See 1 fas
cells; cells;
DMA HPLC»Hlgh
-------
-48-
and the of
1n the 5 and Illustrate a of
and limitations to biological 1n (2,3).
The biologic rationale for DMA is lesions,
if unrepaired, can a mutation. Thtre 1s consfderabli
In cells "Initiates" the of
(4,5); but 1t nay result in of to the
(6,7). resulting In
may 1n
(8,9,10).
Protein as can, 1n theory, act is a readily
available for DMA. Proportional Ity protein and DMA
binding has for a of (11,12,13).
Addycts are generally monitored 1n peripheral blood cells rather than
tissue, for only § few {e.g.,
and els platinum) is ind/or
lewels ire at {14,151,
METHODS
Techniques to carclnogen-ONA Indyde ysing
adduct-speciflc polyclonal or monoclonal
and
P-post1abell1n§, Carcinogen-protein nay be
antibodies and gas The sensitivity of
the DNA to 1s in the of out per 10 -10
nucleotldes. Those it carcinogen-protein
quantification also to sensitivity for
(16). Identification of particular DNA
at low levels Is difficult with analytical
cross-reactivity of as the BPPE-I-DNA antibody
nhich closely related polycycllc
in definitive characteriiatlon of (17).
AND
Experiment*! Involving chronic to
the relationship and
macromolecular binding Is genenlly linear with few (12,2,18,3).
With to carcinogen-DMA and -protein
Investigated in populations with as cigarette
PAHs, and nut, iflatoxln and i-nltrosamines, c1s
platinyn, psoralen, 4-a«1nobiphenyl, propylene oxldt, vinyl chlor1de°^"nd
(3).
-------
-49-
far the feasibility and sensitivity
of the 1n of are by
ability 1n the of
controls, and
illustrate is significant variability In the of
and -protein Individuals with
or 115,19-25). 1n
the involving Is
levels of ire 1n so-called controls"
(19-20,26-29). of for
risk
stm 1n the to DMA
and 1n and
potential in a of Include: identification,
of in¥0l¥ed in risk
extrapolation and improving the and tlweliness of
{19,26,30-321.
1s 1n the following
A. Inter!aboratory validation of as ftas
recently for (331.
B. on the stabllHty of 1n
C. of Inter-Individual In
levels.
0. on the of In cells and
tissues.
E. of levels 1n QUA as well as 1n
for a of different
of
F, of critical or "hot on DMA
to the of
G. of DMA and formation
(e.g., and with and chronic to the
compound!s)},
H. and on the relationship
formation, mutation, and activation.
1. Longitudinal (experimental and on the relationship
levels and risk.
would be molecylar epidemiologies! In populitlons
(sych as to high §nd who
experience a high of secondary cancer, or htawily-exposed
-------
-50-
groups). Biologic could be drawn at the outset and
for future analysis,
J. to as archives of blood, urine, and
tissye for retrospective analysis.
-------
-51-
KEFERENCES
1. F. 1987, Epidemiology: A New Tool In
Prevention, J Cancer Inst, 78,
2. GN, NJ. 1985. and of
to Chew-Heals, Environ 62, 5-18.
3. F. The Significance of DMA and in
Bi§monitQrin§ Studies. Hut Res (1n pressj.
4. IB, Gattonl-CelH S, iClrschiteler P, M. W,
J, Jeffrey A. Cardnogenesls Involves
Hyltiple and Multiple cells 1. The
Laboratory, Nw York, pp.
i. Harris CC» Future Directions In the Use of DMA as
for to
and Carcinogens. Environ §2, 185-191.
6, Hennings H, R, ML, EF, R, SH
Malignant Conversion of Skin Is by Tynor
Initiators and by (London), 304,
67-69.
7. E. 1i84. 1n
738, 219-236.
8. FA, Kidlubar FF. 1985. Forntitlon and of Arylaiini
DNA In Vivo, Environ 62 ,
i. CO, KH, Phillips DH, Activation of c-Ha-ras-1
Proto by In _Vfjro Modification with the Cheiical Carcinogen,
01 o*PfipoxTle , {London}, 310,
ID. K, R, R, K. DMA in
J. Res CUn , 112,181-188.
11. L, E, Osteman-Golkirt G. 1983,
of tenotoxlc and Relationships of Their Effects.
Res 123,
12. HG. and Relationships, 1n:
Berlin A, M, K, Ysalnio H (Eds.), Monitoring
to and -I ARC Sci, Pybl No 59,
Ly§n» pp. 115-128.
13. HG. of as a for
Alitylatlng md Arylitlnf Toxlcol, 56, 1-6.
-------
-52-
14. SJ, MW. and of
S2P
15. E, SH. Zwelllng LA, RF, Polrter MP.
Quantitatlon of II (ds platln)
-DNA-tntrastrand 1n Testlcylar and
J Pin 77,
16. SR, PL. Biological to the Evalyitlon
of Risk; of 1n lexical, 4,
S367-S370.
17. RM. of New for of
to Population Monitoring. its
(1n press).
18. Polrler MC» FA, 1987, of
1n and Exp 31,
1-10.
19. F, Rt HK, AR, M» 0,
H, Van J, DMA and
In and J
Inst.
20. f, K, TL, D, Kelly G, RM.
1987b, of Polycycllc In
Cells of
21. K, RR, CC.
of 1n Cells.
45,
22. A, G, C, K» Trfvtrs GE» HJ,
Harris. CC. of Polycycllc 1n
the Urine, in
and to the in
to of Polycycllc In the
Rts 46, 4178-4183.
23- MS, PL, SR, M. 1987.
of in and
Cancer Res 47,
24. IP, HF. 32p Of DMA
1n Oral Cells. 7» 111-5-1120.
25. Phillips DH, A, PI. DNA 1n
Human and Perlphtral Blood Carcinogenests 7,
2071-2075.
26. BA. 1980. An to the of the Risk to Han
DNA Toxicol, 3:271-281.
-------
-53-
27. Wright AS. 1983. Molecylar Dosimetry Techniques 1n Risk
An Industrial Perspective, in: AW, Schnell RC,
Miya TS {Eds.). in the Science and Practice of
Toxicology. Elsevier, pp. 311-318,
28. Tornqvist M, Os Golkar S, Kaytiainen A, Jensen A, Farmer
PB» Ehrenberg L. 1986, Ttssye of Ethylene Oxide in Cigarette
Determined Adduct Levels in Hemoglobin.
Carcinogenesis, 7, 1519-1521.
29. RB, RM, Santella RM, Cefalo RC, Avltts TA,
R 1986. Detection of Smolcing Related Covalent ONA Adducts
in Placenta, Science 231, 54-57,
30, BA, BE, IB. Banbury 1982.
Indicators of Genotoxic Exposyre; Report No. 13. Cold Spring Harbor .
Lab, Cold Spring Harbor, NY.
31. MAS Briefing Panel. 1983. Report on Effects of Hazardous
Chemical Exposures. National Sci, Washington, DC.
32. Sobsel FH, 1982. The Parallelogram; An Indirect for the
of Genetic Risks from Chemical Mutagens. In; Progress in
Mutation Research (Bora KC» Douglas GR-, ER. eds.). Elsevier,
pp. 323-327,
33, Santella Rm» A, F, et al. 1987, Intelaboratory
Comparison on Antibodies and Immunoassays for Benzo[a]pyrene Diol
Epoxide-i Modified DMA. (Submitted).
-------
-54-
Ep1demiolog1cal 1n long-term to
can which, on the
and of can of §nd
to and personality to and
irreversible to be an early
of neurotoxldty. led the international
to call for for Identifying and
1n and 1n
clinical
OF AND
An of to
applications to this 1s the of §nd
The of this field 1s to how function is
out by the as well as how various neuropithological
conditions, is Alihelier's and Korsakoff's
cognitive 1n of Is
By fully i of all in the
basic is with the neyroblology of leirnlng ind
It 1s not surprising 1n this 1s occurring
it a This will briefly highlight specific
in this field i
on neyrotoxicological
Analysis of the neyrob1o1o§y of leirnlng his
(1) key brain I.e., brain are
essinttil for different of (2) "circuits" in the
brain, I.e., the of
information results 1n the of and
{3} 1.t., the of the
during learning, and the and cellulir which
under!1ne The first of has hid, as one of Its
concerns, the of how to from animal of cognitive
dysfunction to The latter two
primarily with analyzing the at molecular levels,
In the 5-7 years, discoveries in ill of
in the of extrapolation two forms. One has
to develop behavioral in animals which are to
which are to cognitive function 1n The
form, and the one which we will here, has to apply
-------
-55-
behavloral to which are to which ire will
behivforally and neuroblologically, in For
It has recently delafed-non-mitching-to-saiiple, i
which is i indicator of with
limbic and frontal cortical in and prinates, 1s also a
sensitive indicator of with similar in .
clinical is the use of
conditioning to learning deficits,
and Alzheimer's which by of
eyeblink conditioning 1n rabbits. 1n
establish a link the
analysis of cognitive 1n and its
to research, at validating the
appH of new to the of risk
will substantially "on the of how
can be to risk to populations, following
to solvents and pollutants.
The important the
sophistication of neyrotoxlcological 1s the Identification of
neural circylts sybserving learning. The of this 1s the
neurobiologlcal of conditioning. This Pawlovlan
conditioning has for neurotoxlcologlcal
including: (a) the of of Its
properties, which It to
associative to In a
single experimental preparation; (b) the ability to directly
qyantltative of and behawlor, on-line and
in real time; (c) the ability to directly the of
conditioning In §nfrails'and (d) the of
electrophysiologlcil loci for, In the
brain EEG activity scilp
Important offered by this 1s the
of we now Its essential circuitry
in the brain and ye also a the
effect of on this of and this
freatly oyr ability to the of
neurotoxicologlcil If an a
behavioral effect, we i of to look for Its
and effects, and ylt1»ate1y its s)
of action. Conversly, 1f a an effect on a
or we functional to for
in of the of or cognitive which be
impaired. Investigators to use Pavlovian
of this kind as in the neurotoxicologlcal
just this (1987), the
has applied to the study of with aluminum
toxicity.
One final which is mentioning is the use of the i_n
vitro brain slice technique to study neural plasticity,
ITicTrophysiological studies of hlppocampal slices i
long potentlation (LTP), has very
influential as an for studying the synaptic
-------
-56-
of learning. In LTP 1s, In effect, in In efficacy
*1th of the cellular ind
of LTP a of i
(the or
of the nay the of LTP, ind may
disrupt cognitive function 1n rats. 1s of may be
of leg.,
chemicals). It is likely in this
may be as a of
for their ability to and
of characterizing the of any
are foynd.
SUMMARY
In of 1n
i for the analysis of
1s at a
Importantly, a level. It 1$
possible to «i scientific subdlsciplines,
including cell biology, , neyrophyslology, and
ind 1n i and way to
(a) identify the ri»k to
n§rm¥Fc¥pTt1 ve function or (b) the of of
as the wKTcF^reTiown to loss,
and
-------
-57-
USE OF IN
of
which his for application to a variety of
2 for others). This will
new applications in neyrotoxlcity.
to a foreign elicits an
by production of are proteins
that with are of
inducing antibody formation). anttgenic can
viruses, bacteria, proteins, or like envlronnental
chemicals. Ant1gen-antibody reactions ire highly specific,
the specific to biology. It 1s this specificity of the
intigen/antibody that has exploited by the
scientist with applications ranging curing Polio to understanding the
molecular of catalysis.
Antibodies are in the by B lymphocytes (B-cells), each of
which its own antibody. In theory, as as 10 million
antibodies cm bt by a 1n to a single antigen.
with a an an^
contains one B-cell can
only one but are B-cells
epitope, this fs to as a polyclonal (many
cells) antibody.
The fusion of Kohler and Milstdn, for which
the Prize, was to the 1 Imitations
with the use of polyclonal antibodies (e.g., con nation,
heterogeneity, limited supply). The antibodies by Kohler and
Mil stein referred to as monoclonal by a
single {mono} B-cell line {clone}, antibodies
including: 1) speclfldy clone only one
specific antibody}; 2) unlimited sypply largi of
antibody and can be Indefinitely); and 31 purified antigens are not
for the production of antibodies by definition
only a single antlgenlc determinant).
ftonoclonals to define, localize, purify, quantify, and
modify antigens. The distinction the yse of monoclonils, is
to polyclonal antibodies, is confer fir
precision and accuracy and are available as essentially , off the
shelf reagents. Thus, It 1s now possible to define with § greater
of certainty This tnit of monoclonals
has it far to identify rare in vivo and ir» vitro
(e.g., tissue cell and typing 1n celTTiTltureTT """One"
example of the application of monoclonals that is relevant to EPA is
the usi of specific monoclonals to identify dioxin In
contaminated soils. Trye pyrficition of antigens from
(e.g., strum, tissue) also is now possible with aonoclonals. Thus,
rare factors or hormones, as interferon, can now be eisily in
-------
-58-
Likewise, of in
H to polyclonil
an chorlonfc for 8y
specific modification of toxtdty or
also be realized. are of dlfoxln
(with antibody to dlgoxin), and with
linked to to cell antigens.
of Monoconal sto
The of on nonoclonal followed and
Milstein's original in 1975 are now beginning to revolutionize
ntyrobioloay by providing the tools with to the
cellulir and subcellular organization of the Thus, the
Impact of antibody technology on has the
identification of cell 1n the
monoclonal s now which identify previously
of and g11i (the cell of
tissue! which would not to be different yslng classical
of light or electron microscopy. Monoclonals also
crucial for the Identification and of
and to differences
within the nolecule. For example, monoclonal antibodies
that reveal phosphate-containing nonphosphate-contalnlng
neuro filaments, the major strycturil {filament) of ill neurons,
The significance of this i.e., the or
of a single 1s this may be to i
¥ariety of neurological Including Alzheimer's and
also may i to Injury of the
In neyrotoxlcology » It 1s toxicant-induced Injyry to the
or 1s by alterations In
the of specific regions. Furthermore,
within an region, the to injury nay
cell distinguish the cell
comprising the by monoclonal
antibodies, cm be to detect, localize and
ce'-jlar to This can be
by a as
are as specific for microscopically localizing specific
within animals.
Quantitative are with the antibodies by using
monoclonal-bised Thus, through the yse of monoclonal
in /blochenlcal cvalyatlon of
neurotoxicity may eventyally be The possibility exists
the sensitivity and specificity of monoclonal antibodies can be applied to
the and of into the cerebrospinal
fluid and blood is a of neurotonic Theoretically ,
it would possible to 1nexpert$l¥e monoclonal -anti body
for neurotoxlcity In the
population.
In summary, it is clear that cyrrent in neurosciences will
continue to re¥ea1 the extensive cellylir and subcellular heterogeneity of
the on the yse of monoclonal antibodies. The EPA, by
-------
-59-
in will by the
to mS
-------
-60-
A problem In environmental health 1s the non-Invasive
of small or at early
applications of hold for just
In the few since liuterbyr1$ fij was published,
(MR) his rapidly into an
clinical and, also, a of potential*
with high field, (1.5 to 4,7 Tesla) are
available ind ire for and laboratory
animals the
of density, relaxation tines, and the
acquisition of 3-dlraensfonal
types, of and allow the
of or perfyslon (2-5). for of and
Intensity, the (proton) Is for the
production of.orictically all MR Images, The abilities,to
nyclei (e.g. Ma] and chemically shifted nude! (e.g. H In
fat} ind the versatility and
of the
Present day MR of and laboratory animals
detail that, in applications {biologic
and small animals), microscopic levels. In
publications (6,7), of frog and plant
with {voxels) of 0.2 and 12.0 L, respectively.
are it Un1«r$ity In
chemically as as 100 I in
1n fits. The ability to in live
Imaging (is long as 6 hours!, fields
and gradients, pylse and little or no relttlwe
motion. respiratory 1s the to
the liver, the list {no 1s by the
, y$ing a anesthetic, and synchronizing signal acquisition to
respiratory (8,9).
of the of MR are to of
techniques, and are unique. Similar to
{CT} scans, MR imaging 1s non-Invasive ind may be
multiple on the anlia! or patient. In toxicology experiments,
for example, Incorporation of MR Imaging of a of animals could
provide important Information concerning organs* to lesion
{e.g., tumor) and to or modified
(e.g., or of lesions). MR
animals per with conventional for
similar information.
While Imaging on Ionizing radiation are well
established, rapidly (a distinct to MR Imaging
-------
-61-
it its of development), and excellent for demonstrating
structures or (e.g., lesions containing calcium
deposits, MR has distinct and Important
advantages. With eurrtnt and anticipated fields, gradients, and
RF signals, and with the proper precautions MR imaging 1s considered
for patients and technicians (10). Additionally, the MR signil, unlike the
penetrating of Ionizing radiation, contains Information 1n addition
to of tissue (in this case, density. The signal 1s
by the at which relax 1n relationship,to the
nolecylar lattice (Tl, spin-lattice, longitudinal relaxation! and to
other (T2, spin-spin, transverse relaxation).
are Influenced by the composition of the tissue {probably by the
and motional of molecults}, the resyltlng can
permit distinction of are similar In density but differ
In relaxation
Although not a consistent finding, malignant frequently Tl
and 12 relaxation greater of benign or ndmil
tissue, concerning the Inability of MR
Imaging (relaxation to distinguish pathologic entitles
(111. This nay be partially related to the acqyisltlon of
the signal from tissue si lets that, of slice thickness, Include
and normal within and adjacent to the lesion of
Interest. In animal it University, this possibility is
being explored by excising very thin (only 1,26 mn thick) tissue slices 1n
rats. While signals thin slices art and Imaging sessions
are relatively long, the thin sections with high resolution greatly Improve
the selectivity, and, hopefully,, the discriminating ability of the
AND
In clinical medicine, MR Imaging cowpllmtnts and frequently the
performance of other Imaging methods. MR imaging excel!s In demonstrating
ntoplastlc, dentyellnating, and degenerative of the central
system, of the sy$cetib1Hty of the thyroid md
parathyroid glands to Ionizing radiation, MR imaging is a preferred
for nation of tissues. Respiratory and cardiac gating
to prodyce excellent diagnostic of the heart,, thoracic blood
vessels, and lungs. MR of liver, kidney, reproductive organs, and
pelvis routinely a variety of neoplastlc and non-neap!astic
processes. Current and futyre will incorporate the use of
faster scanning sequences, 3-dlraenslonil Imaging, of perfyslon
and flow, contrast Imaging with jjn vitro spectroscopy of
different nyclei (e.g., 1PS C, Nas FJ» chem1caT~sh1 ft Imaging (e.g.,
permitting proton of H. 1n fat), and,
possibly, myltinuclear Imaging (e.g., P, N). These developments, in
addition to Improving the sensitivity of detecting lesions, will allow
Imaging to be with j_n vivo metabolic studits can characterize
biochenical activities 1n a "FegToi~of interest.
In toxicologic experiments, techntqyes that allow
prolonged anesthetization of rats (as long is 6 hours) associated with
respiratory and cardiac synchronization for thoracic and abdominal
-------
-62-
imaginf. High field (300 MHz, 7 Tesla) are being developed and
that a theoretical resolution of 10 M. of active
include the of RF coil designs, and the use of
stronger field gradients, surface and implanted coils, and contrast agents.
Within a few years, increases in resolution should permit, for example, the
visualization of renal glomeryli, preneoplastic hepatocellular foci, and
nyclei in the br§in. With developaents, Lauttrbur's closing
in his 1973 paper would remarkably prophetic, "Zeugmatographic
techniques should find useful applications in studies of the internal
structures, states, and compositions of microscopic objects,"
-------
-63-
REFERENCES
I. Layterbuf PC. Formation by Local Interactions:
Employing Nuclear Resonance, 1973;
242:190-1,
2. CJ» WR. The Evolution of Nuclear Magnetic Resonance.
In: Introduction to Magnetic Resonance Imaging, Denver; Multi-Media
Publishing, Inc. 1984:1-12.
3. Andrew ER. A Historical Review of NMR and Its Clinical Applications.
Br Ned Rev 1984;40;115-9,
4. Damadian R. Tumor Detection by Nuclear Magnetic Resonance, Science
5. Lauterbur PC. Cancer Detection by Nuclear Magnetic Resonance
Zeygmatographic Imaging. Cancer 1986 ;57: 1899-1904.
6. Aguayo JB, Blackband SJ, Schoeniger J, Mattingly MA, Hinterraann M,
Nuclear Magnetic Imaging of a Single Cell. Nature
1986 ;322: 190-1.
?, Johnson GA, Brown J. , .Kramer PJ. Magnetic Resonance Microscopy of
Changes in Content in of Transpiring Plants. Proc
Acad Sci USA 1987 ;84:2752-5.
8. Hedlynd L, Oietz J, R, Herfkens R, et al . A Ventilator for
Magnetic Imaging, Invest Radio! 1986;21:18-23.
9. Hedlund L, Johnson GA, Mills GI. Magnetic Microscopy of the
Rat Thorax and Invest Radio! 1986;21:843-6.
10. Saunders RD» Smith H. Safety of NMR Clinical Imaging. Br Med
Bull 1984;40;i48-54.
11. Johnston DLS Liu P, Wisner GL, Bi, et al . Magnetic
Imaging; Present and Future Applications. Can Med Assoc J
1985;132:765-77,
-------
-64-
Luster
In a broad irmunotoxlcology can be as the study of
(inadvertent) effects of envlronnental chemicals, therapeutics or
biologicals on the The of effects that nay occur
include {i.e., or
hypersensltlvlty (allergy) in Instances, autolnmunlty. A large
of Information has over the 10 years that to
certain chemicals or can dysfunction and alter
resistance in animals following and sybchronic
exposyre. Examples of are listed 1n the attached table, The
extensively of environmental Is the
aromatic .(PHAs), Including polychlorlnated biphenyls,
polybromlnited biphenyls, chlorinated dlbeniofurans §nd the of
this class, chlorinated d1benzo-p-d1ox1ns.
the variability the toxic
of 1n laboratory animals during
or adylt life with and, 1n pirtlcylar, dibenzo-p-dloxins
Indicated that the 1s one of the sensitive for
toxicity. These effects are characterized by thymlc and and
persistent of cell-media ted (T. cell) and
featyres of neonatal Laboratory further Indicated
the cell for by 1s the epithelium
which 1s for T cell only a United
of reports Indicate dysfynctlon following to PHAs,
the effects to be remirtedly similar to which
in animals. For example, sypprisslon of a hypersertsltiv1 ty
and susceptibility to respiratory Infections
1n who accidentally polychlorinated
blphenyl/dibinzofyran-continlned rice §11. of this
deregulation by PHAs his 1n Michigan residents
inadvertently polybromlnated blphenyls. ThiSi Individuals also
persistent of cell-mediated Irani unity with
of null cells, reflecting the of
Gills. Althoygh long-term of
polybrominated biphenyls re«i1n to be determined in hynans, early data
Indicate a correlation alterations and
incidence,
Thus, 1t early laboratory In
a of the Iranunological dysfynctlon is
in following Inadvertent exposyre to these compounds.
-------
-65-
or
11 MB
Class
v
(Mr
Laboratory
*
PCB +
FB0 +
1CT +
*
*
+
+
+
*
BftP *
+
*
*
*
+
+
T: :
SQ2
+
;;" ' +
t
M.S.
.
M.S
M.S.
M.S.
M.S,
U.S.
N.S,
N.S.
N.S.
+
N.S.
4-
M.S.
U.S.
«„!. • +
-------
-66-
and WUcox
BACKGROUND
Public scientists long the
of pollution. One
ind troubling has are of on the
earHtst of pregnancy. This can Include environmentally-
early abortions/fetal If way to the
earliest of pregnancy, of ,
, or drug be easily and
It is 151 of clinically-recognized
end in loss {spontaneous abortion). The risk of loss has
to b6 in populations with occupational.
environmental, etc,, clinical don't tell the
story; clinically-recognized only a portion of all
losses. There are at as earlier as
Thus, a which could
pregnancy very eirly define its ending precisely could help pinpoint
chemical or other environmtntal exposyres night Involved
In ending. The application of new with chorlonlc
offers possibilities.
METHOD
Detemination of early loss reqyfres sensitive and
specific for identifying The of
to one of the subunlt of HCG has vastly
the of HCG to early pregnancy, HCG 1s by
the starting at the diy fertilization. HCG
1s quickly in the mother's urine and is by 1mmunometr1e
For thH reason, HCG are the of studies of early
Tni3 1s to the
of the HCG molecyle. The is up to one
sensitive than any previoysly available This
sensitivity has to be Important up to
of early losses a 1e¥el of HCG secretion could
by
IMPLICATIONS
Eifly loss way be one of the earliest signs of
to or toxins that reproduction. It should be
to streamline this of study, collecting yrlnes only on
early loss is likely to be This could be
to high-risk groups of 1n occupational or other settings
toxic effects on reproduction are suspected. are now
able to HCG in yrint to the levels occyr in
non-pregnant are just now beginning to be
-------
-67-
1n for the of
loss. This 1s in exciting new applied in
Is the of 1n
biology. This may be a for and
and clinical are 1f we ire to 1n
vulnerability to
exposure.
Further and is in this -- as a high
priority -- of are
can the of clinical If
may Inclydi of the and
the microelectronics Industry.
-------
-68-
8
OF
Hoel/Mlchiel
AND RISK
Sinct relevant ep1deffl1o1o§1c and clinical Information are lacking
on the potential health with to a specified
or chemical, laboratory animal usually the
for qualitative and risk The
majority of inlmal-based, Is qualitative 1n nature.
That 1$, laboratory or Identification of a
as a potential 1s sufficient, 1n and of
itself, to control or future of the public to
the or in question, and no of the of
the risk involved In the may be (*.g.,
regulation of potentially the
1t 1s the of In the
qyant1ficat1on of health risks that 1s of scientific
and
Art1nal-ba$ed, two
or be
extrapolation, by the high levels typically 1n
laboratory animal and, of the
ultimate Is with the risk to the single
1n 1s the of the
specific or to be 1n
determining the risk or the level for the
consideration. In cardnogenes1sf may
as far ts 1s or further
Insights into the underlying the carcinogenic
Certainly the for on the meaningfyl Incorporation of
molecular and risk, 1s well and It
offers in opportunity to in the
quantlflcation of potential risk on For
noncarcinogenlc or Is definitely i to
the "safety factor" to which has
the the mid-501s, 1n Instances, to
the of quantitative similar to in
ctrci nogenesis.
Regardless of the toxicologic of Interest, howe¥tr, it 1s
clear that, increasingly, will be on the
or extrapolation closely reflect the underlying
biological mechanisms. For example, 1n cardnogenesls the question of
"primary" "secondary" or "indirect" of action and their
on the risk 1s with
who the litter traditional
low-dose extrapolation (1), On the who out of
-------
-69-
or on the for
levels for may
to the biological ynderlie its giving
particyTat to the of thresholds* For 1f one
a threshold is the
i (biological),"no effect" or a or
level the are minimal"? It to the
population as a or Individual to Individual? (In the
latter the nay be
one for which no threshold That 1s, 1f 1 evils vary
indlvidya1s9 the "population" level to the
for the stnsittve 1ndi¥ldyi1 tn population, which, for
all be indistinguishable t
level.! of 1s 1s a (is
to traditional) for the of any
to be an In
of levels (2).
The of may well as
scientific as the of the
Certainly, the utility of the
for Identifying risks 1s broadly
within the scientific [e.g., see the (3)
the interpretation of to
carcinogenic risk or clinical are not available].
Is no unlversilly of
the results 1n to 1s usually
is to and risk is
1n of the Yet,
e.g., on can by as as 40-fold (4)
on are in of an
daily or a ng (divided] by
weight. Furthermore, one to rely on
a as the for extrapolating risk
an 1s only an
for the variety of can to
In (e.g., In llfespan, size,
profile^ genetic etc.). In
the quantitative of taxied ogle will
on the use of nolecylar and For
the use of or nolecylar dosinetry,
scientifically feasible, to the "biologically
could significantly the
extrapolation of toxlcologlc
for quantitative risk estimation
and are Increasingly to epidemic!ogle as well as to
laboratory animal resylts, particularly In the of cardnogenesls.
of the Inclyde fitting of the
to DoTTs 16}, Day and Brown's y$e of the to
a of risk as
-------
-70-
and radiition early, or early and late
of the 17]» Ill's (6) use of and
to the of
site-specific syrvivors, and their use of
linear, linear-quadratic and to predict
risk with Ionizing radiation. While the use of
obviously elimlnatfs the for extrapolation, nay
not be sufficiently sens1tl¥t to allow one to
or, in instances, to if any
risk to be low or levels of
A of may be to increase the sensitivity of
the available epidemlologlc For Instance, Initial it
risk Identification and could be on sens1tl¥e
within the population as the old or young,
indivldyals with insufficient Individuals suffering
concurrent or Inherited deficiencies, and individuals also
to risk factors for the toxlcologlc endpoint or effect
of Interest.
Recently, a new speciality his In the field of epidemiology,
which 1$ as nolecylir or biochemical epidemiology. One of
the primary of molecylar 1s to laboratory
for the identification and characterization of
to epidcmlologlc field studies, so as to clarify the of
underlying relationships, I.e., relationships
and or toxicploglc (8). Specifically,
may provide quantitative of (e.g.,
blood levels}» specific (e.g., ONA formation),
biologic and early or frank to replace the subjective
and qyalitative 1n ep1dem1olog1c
Investigations (e.g., histories
and classifying as tlther "exposed" or
"unexposed".)
While Interest 1n ind and application of biochemical 1s
increasing rapidly, validation of their use for epidemiology 1s currently a
major and 1t 1s likely to to be so in the
future. [Among the be In any validation
exercise the determination of marker sensitivity, specificity,
predict!¥ity, of nomil or baseline values, whether marker 1s
reflecting cyrrcnt or cumulative exposyres, or and
cumulative or noncymulative biological (8),]
POPULATIOM
The last in the qyantitatl¥e risk 1s the
of the overall risk for the popylatton of or,
alternatively, the of an level for
population. of the uncertainties Involved 1n using experimental
animal or epidemic!ogle 1n Identification particularly, 1n
dose-response modeling and low-dose risk estimation
enumerated. If a can be for the of a
-------
-71-
tnreshold and a factor approach Is elected, 1t 1s
Important to that failure to adequately for the
ynknown, underlying threshold can result In a proportion of the
population having their Individual threshold values falling the
estimated level In Instincts (2).
Another significant factor that must be 1n developing
population risk is the or estimation of
levels within the population yrtder evaluation. There art a of
potential or yncertalntlis typically Involved 1n the estimation of
population exposyri levels. Exposures vary considerably
Individuals or for a single Individual across time, so that the use of
exposure levels may not be very representative of the
histories of Individual population While use of worst-cast
exposures providt in on the actual levels of exposure
encountered, 1t can also lead to an overestimate of the popylatlon's health
risks and certainly a of uncertainty
estimates. The uncertainty 1s or worst-cast
estimates are multiplied by the risk per unit
to obtain an overall estimate of population risk. For example,
though worst-case may the
experience of much or possibly all of the popylatton of Interest, "iveragf"
risk per unit estimates may significantly the risks of
the susceptible of population.
the uncertainties Involved In quantitative risk
estimation and concern for the health of the popylatlon often
led to the overuse of worst-case or upperboynd 1n quantitative
risk est1mat1on--assumpt1ons that result 1n is undyly
conser¥itive estimates of the popylatlon risks. However, are other
investigators (9) who national the of
health risks has to be alnostly exclusively on cancer
risk, and as a result, other (perhips less quantifiable) of
human disease or dysfunction may have received Insyfficient attention: (See
Appendix), If this 1s the cise, then, 1n any specific situation the
estimated "acceptable", "virtually safe" or "minimal risk" for
cardnogenesls may still entail an unreasonable le«l of risk of
health the estimation has on
conservative assytnptlons.
The OSTP (10) tnd other science policy reports
the for qualitative and quant1tatl¥e characterization of the
uncertainties of specific risk (e.g., consideration of the Impact
of model selection, the use of one set of laboratory over another, the
choice of a particular species as being most representative of humans,
etc.). Also Important are considerations and specification of the
assumptions ynderlylng a particular risk assessment (e.g., the construct of
an estimated lifetime dally so animals continuously
at a constant throyghoyt their lifetimes might be to
estimate the risk in hunans who miy received Intermittent at
varying for only a portion of their Hfespan). The continued
attention to/stress on descriptions of specific uncertainties and
assumptions involved 1n any given risk assessment and to their potential
impact on the estimation of risks has helpful to
-------
-72-
with regulatory responsibilities for rational and decisions
the fate of the consideration.
-------
-73-
REFEREI4CES
3.
4.
5.
8.
9.
Hoel , D.G., Baseman, O.K., Hogin, M.D., Huff, J., and McConnell ,
E.E. The Impact of Toxicity on Carcinogenicity Studies:
Implications for Risk Assessment. (Sybmitted for Publication)
Portier, C., and Hogan, M, (1987). An Evaluation of the Safety
Factor Approach in Risk Assessment. In: Mclachlan, J.A. , Pratt,
R.M. , and Markert, C.I. eds, Banbury Report 26; Developmental
Toxicology: Mechanisms and Risk. Cold Spring Harbor Laboratory,
New York,
International Agency for Research on Cancer (1985). Preamble {p,
ZO). In; Volume 35: Polynuclear Aromatic Compounds, Part 4,
Bitumens, Coal-tars and Derived Products, Shale-oils and Soots,
IARC, lyon, France.
Office of Technology Assessment 11981), Assessment of Technology
for Determining Cancer Risks from the Environment. Washington,
D.C.; Government Printing Office.
Doll, R., and Peto, R. (1978), Cigarette Smoking and Bronchial
Carcinoma: Dose and Time Relationships Regular Smokers and
Life-Long Non-Smokers, J. Epid, Conro. Health 32: 303-313,
Day, N.E., and Brown, C, C. (1980), Multistage Models and Primary
Prevention of Cancer. JNCI 64: 977-989.
National Academy of Sciences, Committee on the Biological Effects
of Ionizing Radiations (1980). The Effects of Populations of
Exposure to Low Levels of Ionizing Radiation; 1980, Washington,
D. C.: National Academy Press.
Schulte, P.A. (1987). Hethodologic Issues in the Use of Biologic
Markers in Epidemiologic Research, Ant. J, Epid. 126; 1006-1016.
Silbergeld,
1399.
E.K. (1987). Letters: Risk Assessment, Science 237
10, U. S, Interagency Staff Group on Carcinogens (1986), Cl
nogens: A Review of the Science and Its Associted
inlPt. FHP fi7 • ?nU7ft?_
Circinogens;
Principles,
1986), Chemical
EHP 67: 201-282.
-------
-74-
Of AND
Chernoff and
The of basic on cancer and non-cancer within
any orginizitlon 1s a variety of as
Congressional the given organization"s operational policy, public
perceptions and concern, ongoing Identification of potential §nd
to extent, the of disciplines by the organization's
scientific staff. All of an 1mp°act on scientific
in their designing and a basic to
their organization's now and In the future.
Generally, 1n legislative authority EPA to
evalyiti a of potential health effects associated with
to environmental chemicals ind Insults, Rartly legislation
specific health to be irtdpolnts. It 1s,
therefore, EPA's policy which dlrtcts to specific of
for environmental a public Institution, EPA Is
influenced by the and concerns of the public and Industrial
of chemicals, Consequently, EPA
Its administratfve and regulatory policy to
For years the primary envlroontntal health concern, as
by the public, the possibility of chemically-Induced cancer. The
for this concern Include the and Irreversibllity
of the Its for debilitation and lethality, and
the chaiicals to which is prevalent
cm in laboratory animals. As a result of
concerns the body of that has years,
EPA's (as well as regulatory regulatory policy has been
largely driven by as the htalth endpolnt of greatest severity.
the however, it has Increasingly
art other health endpolnts which nay be
and by to environmental agents. The methyl
mercury- of birth in Japan, the incidents of
delayed neuropathy in the Middle East, and the occurrence of sterility
in occupattonally to chemicals 1n the USA all
to alert the public the potential risk of to
may require consideration of health endpolnts. The of
this realization has a broadening of the of concern and a
simultaneous of to additional
Along with this has an increasing to
consider during the formulation of regulatory
policy.
Tox1co1og1sts in the public and private also
identified other and susceptible populations that are at
potential risk from to environmental These realizations
lead to considerable for research 1n as
-------
-75-
immunotoxlcology, herltible ind and geriatric
Additionally, and the public
increasingly the of lifetime to
relatively of § of
to i of the
of is as the
to risk.
Finally, are two of the and
the scientific of The
translation of Into risk 1s an
difficult While a is desirable, the
regulation md of faulty letd
to finclydlng
a in the of life
of and
is the Indicates,
now and in the future will be
to the scientific and of risk The
of a of the
for and non-cancer 1s yltimttely the rational «ay in
which to foraylate policy. This to i continuing
for
The allocations the
for simpler, and of
testing. Thi of and of 1s
fir in of ability to for by
by the the use of
animals in i to the of
alternative
The EPA efforts 1n greatly
the last for the listed
has led to i and non-cancer 1s
impossible to since art so factors go into
the of this Ctrtalnly, § allocation to
and h« the to utilize a
of health in the fenny lit! on of regulatory policy.
Long-term Into both and 1s
recognized is 1f the Is to a
policy In the possible,
consider and in the
will multiple tox1co1og1ci1 the
of and se¥er1ty of effects will be
attention. Efforts will be to ind lexicological
in a fashion. win the of
structure-activity and modelling, design, §nd
of as well as endpoints.
-------
-76-
6
This century has the of abnormalities 1n early growth
and development, chronic and cancer as the major
of morbidity and mortality 1n the Industrialized nations of
the world. Initially, often as the result
of heredity or the natural of the aging process.
recently, has a rtcognttion
frequently important or risk factors 1n their
etiology.
of environmental risk are either directly
by or subject to their manipulation. They include chemical and
physical in the air, water, supply, drygs, products,
and workplace. While of the of risk
are difficult to or verify, 1t his ¥arioy$ly
i significant of the two million Individuals who die
year in the United may had their lives to
by the effects of air pollution; that pollutants In oyr drinking
water nay play a role 1n the of and disease,
which are the two leading of 1n this country; and the
collectl¥e of and raiy now be
a level of typically with
Therefore. and regulators are
Increasingly to Identify risk factors
and §r eliminate their effects,
Attention has on of the cin
be one to the Impact of environmental
on health. Often, relevant epldwrfologlc and clinical
Information on the potential health with to §
specific or will not be available.
is available, 1t may not be sufficiently sensitive or
specific to allow an to
that to the unknown, underlying relationship
and In the available may
not permit one to 11 any health risk to be
with low or Itvels of As a result,
laboratory anintal will constitute the primary basis for both
qualitative (I.e., Identification) and quantitative risk
estination,
of the high {often maximally tolerated) typically
1n laboratory quantitative risk
estimation on Involves two
be low-dose extripolatlon and extrapolation. In
instances (e.g., when the of Is i carcinogen or mutagen)
mathematical modeling will be to low-dose risk estimates,
and choice of a particular nay a significant impact on the
magnitude of the risk. In a threshold may
-------
-77-
be ind a to
levels. This clearly a of
and
Ideally, the of be by
Into all of the species-specific
coyld contribute to differences in to the of
the to Is to
and the In mm
are on in scale.
Unfortunately, of the be
justified on biological and significant differences can resylt In
the on the As
our on risk to
and 1,s to the to
the uncertainties with risk and
to uncertainties by luprovlng the biological which
the risk 1s
In to to the
Itself,'Which ind on §yr
efforts to the risks by
are I of
our to the of environmentally-related
are the of
on the majority of the
the Insufficient and training of
our nation's physicians with to and the
surveillance of populations or potentially to
Priority be to 1n a of 1f we
ire to and oyr of the role of
en¥i factors in For
to be to the and of
{particularly non-Invasive for low levels of
to Similarly, we to a
of the biological
environmentally-related to the
of health ind the primary/secondary of
environmentally-related A of of long-term,
activities 1n or nay
direct application to the of EPA
and regulatory on an basis art In
this
Comparison of of (I.e., cellular
during and activation 1n
and chemically-induced may Insight Into
the of formation at the raoltcylar level, In addition,
of the uncertainty invoked 1n of
carcinogenic risk eientuilly be by
comparisons of activation and expression.
-------
-78-
Recent advances in biochemistry and molecular biolofy have led to the
of highly sensitive which may the
quantification of the Internal of carcinogens or 1n the
biologically effective in tissues. This ability to
external exposure or adwilnl levels on a
biologically-relevant basis should e¥cntya11y lead to a clearer
understand!ng of the relationships and or
toxicologic effect for health in the environment.
Recognition of the potential usefulness of biochemical has
led to the of a new field of epidemiology, is molecular or
biochemical epidemiology, has as one of its major goals the adaptation
of laboratory into eplderafologic field studies.
In the fields of neyrotoxlcologj and Immunotoxicology new methodologies
promise to lexicologists to greatly Improve our ability to
central and deficits. The utilization of novel
techniques in molecular biology {e.g., monoclonal antibodies to specific
critical chemical components of systems) promises to allow .improved
evaluations of potential disfunctions.
In the of reproduction one of the important questions
involves the potential of environmental to affect pre-1mplantat1on
loss. Researchers recently Identified an antibody to a sybuntt of the
hormone human chorionic gonadotropin. This advanct enables the
identification of spontaneous abortions at an earlier and with
accyracy was previously possible and may significantly improve
oyr monitoring capabilities.
In addition to identifying specific of long-term
activities that either §re generating or may results directly
applicible to the environmental health issues that EPA from a
regulatory viewpoint, this also to describe the
relationship long-term and short-tern (or Immediate)
"problem-solvlng" research to put 1t 1n perspective. For example, It
is noted that the general philosophy undtrlying basic health research is
that ynderstanding more about the biologic by which
environmental hazards as toxic chemicals Induce effects will
lead, ultimately, to earlier of effects, sensitive
analytical for fully characterizing their potential Impact on
health, and a understand!ng of how to eliminate or, at least,
that impact. The dlstlngyishing characteristic of this basic research 1s
that 1t typically "generic" scientific and 1s not focused
on a specific or concern. Fyrtherroore, it usually
be for a period of several 1t results
may a direct application to regulatory or problems.
The environmental health with the toxic lead 1s to
illustrate the necessity of and role for long-tem research activities In
the of a scientific foundation for
constryctive actions dealing with public health While
toxicity resulting "h1§h" level has long recognized as
an important public health concern, ongoing, long-term basic has
only recently given us the ttchnlcal tools to of the
subtle yet extremely effects of low-level lead exposure.
-------
-79-
Is on a or
it nay to be for i of
any or cm be is
new of the
on the the AT 1f the
is and the of clearly
any 1s i of and
may be the Is Certainly, 1s the
In ind to a
with
It clear, of the {or
EPA an If
not the and 1n the only
to will be to on the
and insights long-ttm This certainly has the
in with to The
will us to in 1s to
stable, consistent for a With
and EPA can
issyes It 1s particularly and
its own findings and of and
institutions to the of critical
------- |