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OCR for page 349
"= ~ 1~ ~ CLl~`C.
deficiencies are known to increase the toxicity of pesticides--including
carbonate carbaryl, parathion, and captanl70--and heavy
metal~.37~98 Nutritional status can influence microsomal enzymes and
thus affect the toxicity of PAHs. Protein deficiencies can lower AHH
activity,l°l and the type of dietary protein can affect AHH acti-
vity.36 Nutrient deficiencies are observed in both childrenl25 and
adults;189 deficiencies in iron, vitamin A, and vitamin C are the most
prevalent. Whether these deficiencies play a role in PAH-related
effects in humans is not known. Deficiencies or alterations in vitamins
(vitamins A and C) can influence the incidence of PAH-induced cancers in
animal-model systems.8~19,l76 Dietary vitamin A (i.e., retinoids) may
also influence the expression of cancer in humane. 138 The effects of
vitamins seem to be centered on the later stages of carcinogenesis,
especially tumor progression. Chemoprevention shows promise for alter-
ing or controlling inherent sensitivity (or resistance) to carcino-
genesis, but it should be borne in mind that some vitamins, such as
retinoids, sometimes increase cancer expression and sometimes suppress
it.164
Diets high in fat and meat and low in fiber have been associated
with increased risk of cancer, especially cancer of the
^^~ 51.199.200 The effect of dietary fat may be related to
~ - - ~ ~bile acids, which
Jo 1`JLl ~ -
alterations in the concentration of colonic secondary
act as colon-tumor promoters.l50,l5l PAHs can act as cocarctnogens,
comutagens, or promoters, but whether they play these roles in humans
and whether the nutritional status of the host alters these roles are
not known.
7-11
~. ....
OCR for page 350
TABLE 7-1
Studies Suggesting Correlation between Carcinogen Metabolic
Capacity and Cancer Susceptibility in Humans
Disease Tissue Assayed Reference Comments
Lung cancer Lymphocytes 72 Assay only for "inducibiIity"
Lung cancer Lymphocytes 49 Radiometric assay; 11 cancer
patients monitored
Laryngeal Lymphocytes 185 No controls
cancer
Lung cancer Bronchi 53 BaP binding to DNA higher in
bronchi from lung-cancer
patients; large individual
differences
Renal and Lymphocytes 186 No controls
ureteral cancer
Lung cancer Lymphocytes, 106 Dichotomy of AHH in ly~pho
PAMs cytes and PAMs in lung-cancer
patients
Lung cancer Lymphocytes 32 -
Lung cancer Antipyrine 1 -
-(half-life)
Lung cancer Lymphocytes, 107 Correlation of~AHH depended on
PAMs, patient--lung cancer vs. normal
lung tissue ~
Lung cancer Lymphocytes 39 Absolute AHH activity dominantly
inherited; values given relative
to "standard" panel; no AHH
values presented
Lung cancer Lymphocytes 4
Lung cancer Antipyrine 71
Leukemia Lymphocytes 11
7-12
Inducibility determined by non-
induced AHH activity
Antipyrine half-life related to
cancer and smoking
Susceptibility related to low
ARH
~..
OCR for page 351
TABLE 7-2
Studies Suggesting Lack of Correlation between Carcinogen
Metabolic Capacity and Cancer Susceptibility in Humans
Disease
Lung cancer
COPD, chronic
bronchitis
Lung cancer
Laryngeal and
lung cancer
Lung cancer
Lung cancer
Lung cancer
Lung cancer
Tissue Assayed Reference
Lymphocytes 127
Lymphocytes 110
Lymphocytes 67
Lymphocytes 194
Lymphocytes
(BaP binding)
Lung (organ)
cultures
Antipyrine
(metabolism)
Lymphocytes
66
188
91
7-13
Comments
Progeny vs. spouse; cancer
patients showed low AHH and
were not tested
Smoking, not cancer, associated
with high BaP metabolism; high
AHH correlated with lymphocyte
stimulation.
Measured AHH in disease-free
subjects; 40t on medication;
lymphocytes from all groups
grew well.
BaP-macromolecule binding
measured.
HPLC analysis of BaP metabolites
· · .
In six cancer patients.
Nine hospitalized patients used.
-.. .. .. . .
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Representative terms from entire chapter:
hydrocarbon hydroxylase
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10 Genetic
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Gradually increasing polygenic risk
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~ I t .
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Percent of Population
FIGURE 7-1. Interplay between genetically controlled
variations and environmental exposure leading to cancer
susceptibility. The population of humans is viewed as
a sigmoidal curve where the extremes are either
genetically resistant or genetically predisposed to
cancer. The shape of the curves would be expected to
change for given subpopulations that contain higher per-
centages of genetically resistant or genetically predisposed
persons. Reprinted with permission from Lynch; 5 copyright
Academic Press.
7-16
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EXPOSURE TO
AGENT
| INCOMPLETE OR NO
| EXCISION REPAIR
_
~ r
_ ~
DNA REPLICATION AND CELL DIVISION
[::
FURTHER DAMAGE
IN NEW DNA .
. i.,,
·e_
Deed
| INCOMPLETE OR NO
| POSTREPLICATION REPAIR | | ~=REPLICATION REPAIR |
DAMAGE TO
CELLULAR DNA
1'_
_ META80LIC
ACTIVATION
EXCISION REPAIR
I . , 1
NORMAL, NEW AND OLD
DNA
DNA REPLICATION AND CELL DIVISION
l ~
CYTOXIC, MUTAGENIC,
CHROMOSOMAL EFFECT ,
SOME NORMAL
PROGENY
FIGURE 7-4. Scheme depicting nuclear changes and their toxic
effects. Cytotoxic, mutagenic, or carcinogenic effects are
thought to result from nonrepair or misrepair of particular
DNA damage. Reprinted with permission from Roberts;157
copyright Academic Press.
7-19
| NORMAL l
L PROGENY l
REFERENCES
1. Ambre, J., D. Graeff, F. Bures, D. Haupt, and K. Deason. Antipyrine
metabolism and bronchogenic carcinoma. J. Med. 8:57-70, 1977.
2. Andrews, A. D., S. F. Barrett, and J. H. Robbins. Relation of D.N.A.
repair processes to pathological aging of the nervous system in xero-
derma pigmentosum. Lancet 1:1318-1320, 1976.
3. Arlett, C. F., and A. R. Lehmann. Human disorders showing increased
sensitivity to the induction of genetic damage. Ann. Rev. Genet.
12:95-115, 1978.
Arnott, M. S., T. Yamauchi, and D. Johnston. Aryl hydrocarbon
hydroxylase in normal and cancer populations, pp. 145-156. In A. C.
Griffin and C. R. Shaw, Eds. Carcinogens: Identification and
Mechanisms of Actioon. New York: Raven Press, 1979.
Atlas, S. A., E. S. Vesell, and D. W. Nebert. Genetic control of
interindividual variations in the inducibility of aryl hydrocarbon
hydroxylase in cultured human lymphocytes. Cancer Res. 36:4619-4630,
1976.
6. Autrup, H., C. C. Harris, B. F. Trump, and A. M. Jeffrey. Metabolism
of benzo~a~pyrene and identification of the major benzo~a~pyrene-DNA
adducts in cultured human colon. Cancer Res. 38:3689-3696, 1978.
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9. gingham, E., and W. Barkley. Bioassay of complex mixtures derived
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Cancer mortality in U.S. counties with petroleum industries.
Science 198:52-53, 1977.
11. Blumer, J. L., R. Dunn, M. D. Esterhay, T. S. Yamashita, and S. Gross.
Lymphocyte aromatic hydrocarbon responsiveness in acute leukemia of
childhood. Blood 58:1081-1088, 1981.
12. Borresen, A. L., K. Berg, and P. Magnus. A twin study of aryl hydro-
carbon hydroxylase (AHH) inducibility in cultured lymphocytes.
Clin. Genet. 19:281-289, 1981.
13. Boutwell, R. K. Biochemical mechanism of tumor promotion, pp.
49-58. In T. J. Slaga, A. Sivak, and R. K. Boutwell, Eds.
Carcinogenesis--A Comprehensive Survey. Vol. 2. Mechanisms of Tumor
Promotion and Carcinogenesis. New York: Raven Press, 1978.
14. Brewen, J. G. Cytogenetic studies and risk assessment for chemicals
and ionizing radiation, pp. 97-115. In V. K. McElheny and S.
Abrahamson, Eds. Assessing Chemical Mutagens: The Risk to Humans.
Banbury Report 1. Lloyd Harbor, N.Y.: Cold Spring Harbor
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7-20
16. Carter, D. M., A. Gaynor, and J. McGuire. Sister chromatic exchanges
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1978.
17. Casciato, D. A., and J. L. Scott. Acute leukemia following prolonged
cytotoxic agent therapy. Medicine 58:32-471, 1979.
18. Chaganti, R. S. K., S. Schonberg, and J. German. A manifold increase
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19. Chan, W. C., and Y. Y. Fong. Ascorbic acid prevents liver tumor pro-
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20. Cleaver, J. E. Defective repair replication of DNA in xeroderma
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7-21
8
SUMMARY
The present report attempts to make current the information relative
to the sources (both mobile and stationary) , formation, atmospheric
transformations, biologic effects, and pharmacokinetics of a select group
of polycyclic aromatic hydrocarbons (PAHs) and mixtures thereof, to
identify populations hypersensitive to them and to determine the human
risks associated with exposure to them. The specific PAHs considered were
chosen on the basis of relative concentrations in various kinds of
emission or combustion products or because of some unique pharmacologic
property.
SOURCES, ATMOSPHERIC PERSISTENCE, AND TRANSFORMATIONS OF PAHs
The emphasis of this report is on PAHs emitted from mobile sources,
but these substances are ubiquitous--they are found in terrestrial and
aquatic plants, in soils and bottom sediments, and in fresh and marine
waters, as a result of emission from both mobile and stationary sources.
The total annual release of benzo~a~pyrene (BaP), as a surrogate PAH, in
the United States from all sources is estimated at 300-1,300 metric tons;
approximately 40 tons are produced from mobile sources. It is estimated
that bv the Year 2000 the atmospheric BaP concentration in highly
, ,
urbanized areas- will be approximately O.6 ng/m'.
The concentration of a particular PAH depends on its source (among
other things), but the phenanthrenes (including methyLated derivatives),
the fluorenes (including methylated derivatives), fluoranthene, pyrene,
BaP, benzotghi~perylene, chrysene, perylene, dibenz~ac~anthracene, and
benz~aJanthracene have many common sources. Emission from the combustion
of wood contains more alkylated PAHs than combustion products from other
sources. Wood stoves and fireplaces, nonregulated sources of PAHs, are
important contributors to environmental pollution, particularly in rural
areas with restricted airflow. Wood smoke contains considerable amounts
of particles and adsorbed PAHs, and it is anticipated that this source
will become even more significant wi th the increased use of wood as a
primary fuel.
Of the total motor-vehicle mileage accumulated in this country, the
light-duty passenger car with spark-ignition engine is the major
contributor, although the number of diesel engines is increasing. By the
mid-1990s, approximately 257 of the passenger fleet will probably be
powered by diesel engines. Rates of emission of particles from diesel
engines are about 2 orders of magnitude greater than those from
catalyst-equipped spark-ignition engines. The total PAH emission from
mobile sources in 1979 was approximately 6,500 metric tons; phenanthrene,
pyrene, fluoranthene, methylphenanthrene, cyclopentapyrene, anthracene,
benzofluorene, chrysene, benzofluoranthene, the benzopyrenes, and
8-1
At. . . . .
benzoperylene were major contributors. Nitropyrene and other nitro-PAHs
have also been found as emission products, but whether these very reactive
substances are artifacts of the sampling process or are present in the
initial emission has not been established. It has been estimated that the
total emission of PAHs in 2000 will be considerably lower because of
advances in collection devices on mobile sources.
There are large uncertainties concerning the persistence of the PAHs,
their chemical transformations, and their atmospheric transport and fate,
although some general principles can be derived. There is evidence of
long-range transport from the analysis of cores from sediments; the PAHs
can be transported over long distances in the atmosphere without important
degradation. The principal processes by which the PAHs are chemically
removed are photooxidation, reaction with ozone, and reaction with
nitrogen dioxide. The latter reaction may be responsible for the
generation of nitro-PAHs, some of which are potent mutagens. Of the PAHs
that have been selected for study, only BaP and pyrene have been
investigated in detail with respect to chemical transformations.
Considerably more study is needed.
BIOLOGIC EFFECTS OF SMOKE, EMISSION, AND SOME OF THEIR PAR COMPONENTS
.
It has been estimated that as much as 13% of all human cancer deaths
may be attributed to environmental factors, one of which is pollution
resulting from emission from mobile and stationary sources. Then tested,
however, particles from diesel and spark-ignition engines and
organic-solvent extracts of these particles have not been very toxic to
animals. Only minimal effects on pulmonary function, reproductive
capacity, and glandular or hepatic function have been observed. The
chronic exposure of newborn rats to diesel-engine exhaust appears to
result in some abnormal development of the central nervous system, as
demonstrated by the slower acquisition of spontaneous locomotor activity
and bar-pressing ability; and small abnormalities have been noted in
visual evoked and somatosensory evoked potentials in exposed neonatal
rats. Whether these changes resulted from exposure to the PAR components
of diesel-engine exhaust has not been ascertained.
Although no immunologic changes have been observed after exposure -
rats to diesel-engine exhaust, it is known that some PAHs are
immunosuppressive. In particular, high doses of 3-methylcholanthrene,
dibenz~ahianthracene, 7,12-dimethylbenzanthracene, and BaP reportedly
depress the response of mice and rats to various immunologic challenges
This immunosuppressive effect, exhibited by some PAHs but not by exhaust or
emission, can be divorced from the carcinogenicity of these agents.
Extracts of particles from spark-ignition and diesel exhaust are
mutagenic to Salmonella typhimurium in forward- and backward mutation
assays and in several animal-cell model systems. The extracts were
directly active in the bacterial assay, whereas emission from coke ovens,
roofing tar, cigarette-smoke condensate, wood combustion products, and Pap
8-2
lo. ...
were positive only after metabolic activation--indirect mutagenesis.
After fractionation of the various extracts, the fraction that contained
the PAHs demonstrated the greatest mutagenicity in the bacterial assay. A
major PAH in soot, automobile exhaust, cigarette smoke, and coal fly ash
is cyclopentatcd~pyrene; it proved to be highly mutagenic in the indirect
assay. Indeed, the total mutagenic activity of kerosene-soot extract
could almost be reproduced by cyclopentatcd~pyrene alone.
The direct mutagenicity appeared in part to be caused by nitro-PAHs.
These substances have been found in automobile-exhaust particles and in
cigarette smoke, but not in wood combustion products. The nitro-PAHs were
much more mutagenic than the parent compounds, with 1,8-dinitropyrene
being the most mutagenic of all compounds that have been subjected to the
Salmonella/microsome assay. The mutagenicity of these nitro derivatives
has not been tested consistently in animal-cell models.
The mouse skin tumorigenesis model has been used to assay the
carcinogenicity of extracts of various particles. The condensates from
spark-ignition engine exhaust proved carcinogenic in this model; those
from diesel exhaust were less active. The exhaust preparations had both
initiation and promotion activities with this model. There are
conflicting reports as to whether the tumorigenicity of the extracts
reflected the additive activity of the major PAHs in the condensates.
When tested for tumorigenicity by inhalation and intratracheal
instillation, the condensates proved not very active. The literature is
contradictory on whether the incidence of neoplasia in animals receiving
automobile-exhaust condensate intratracheally reflected the BaP content of
the condensate. Of a series of compounds that were tested for carcino-
genicity in a mouse-adenoma model, 3-methylcholanthrene, dibenz~ah~anthra-
cene, and BaP proved most active.
The effect of alkyLation, particularly methylation, on the carcino-
genicity of various PAHs has been determined with biologic models. The
fluorenes, phenanthrenes, and anthracenes are major components of smoke
and emission, so there has been considerable interest in determining the
effects of methylation of these agents on tumorigenicity. The insertion
of a methyl group at particular positions of the benz~aJanthracene ring
increased tumorigenicity considerably. 9-Methylfluorene was much more-
mutagenic than the parent compound in the bacterial assay system. In the
phenanthrene series, the l- and 9-methyl analogues were more mutagenic
than the parent compound. The methylchrysenes are known environmental
pollutants; although the parent compound is generally inactive as a
carcinogen, the 5-methyl derivative was as carcinogenic as BaP and was the
most potent of all the methylated derivatives when tested as an
initiator. Methylated BaPs have been tested for tumor initiation, and
some (the 1-, 3-, and 11-methyl) analogues have been found to be more
active in this regard than the parent compound. It is apparent that the
methylated PAHs, which are present in exhaust and smoke, can contribute to
. . .
carctnogen~c~ty.
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~;
EFFECTIVE BIOLOGIC DOSE
After administration to laboratory animals, PAHs are absorbed readily
and distributed to various tissues. Nonmetabolized material accumulates
and persists in body fat. This phenomenon may be useful for monitoring
the chronic exposure of various populations to emission and smoke that are
rich in PAHs. Particle-bound PAH is retained in the lung to various
degrees that depend on the size and composition of the particles. Once in
the lung, the particle-bound material can be desorbed and distributed to
other tissues. The clearance of a PAH from an animal-model system appears
to depend on the concentration of nonmetabolized compounds in the fat, the
metabolism of the PAH, and biliary, fecal, and urinary excretion. The
excreted metabolizes of PAH are largely glucuronides, sulfates, and
hydroxylated and phenolic derivatives.
Virtually all tissues can metabolize PAHs, although liver exhibits the
greatest activity in this regard. The initial metabolism is conducted by
membrane-bound cytochrome P-450-dependent monooxygenases that yield
epoxide derivatives. The Latter may spontaneously rearrange to phenols
that serve as building blocks for Later conjugation. The epoxides may
give rise to bans dial derivatives in reactions catalyzed by the
membrane-bound enzyme epoxide hydratase; these dial derivatives may be
excreted unchanged or conjugated as glucuronides. Secondary metabolism by
the cytochrome P-450-dependent monooxygenases yields very reactive diol-
epoxides that can spontaneously rearrange to electrophiles that can
interact with macromolecular nucleophiles, such~as DNA. The activity of
the monooxygenases and epoxide hydratase is genetically determined and is
inducible by exposure of an organism to PAHs; the extent of induction is
also genetically determined.
PAHs may also be activated through an arachidonic acid-dependent
co-oxygenation step involving the prostaglandin synthetase complex.
Through this mechanism, the bans dial of BaP, for example, is transformed
to the diol-epoxide at the expense of prostaglandin G2.
The reactive metabolites of PAHs, such as diol-epoxides, interact
covalently with ONA to form addicts. The adducts of BaP diol-epoxide with
DNA have been examined in lung, liver, forestomach, colon, kidney, brain,
and muscle after oral administration of BaP to mice. Human tissues also
are able to catalyze adduct formation. The DNA-adduct profiles appear
specific for a particular tissue. The amount of BaP-DNA adduct formed in
a particular tissue is not correlated with the susceptibility of that
tissue to PAH-induced carcinogenesis. This is evident from consideration
of liver, a tissue that is not ordinarily a target organ for PAH-induced
carcinogenesis, but one in which adducts readily form. The PAM-DNA
adducts have varied turnover rates in different tissues. The turnover
rate is related in part to the normal rate of replication of the cell and
in part to an enzymatic DNA-repair system. Different addicts are removed
from DNA at different rates.
With regard to BaP, a linear dose-response relationship has been
observed with formation of DNA adducts as the end point. There appears to
be no threshold dose below which adduct formation will not occur. The
administration of a number of inducers of monooxygenases and of the
conjugating enzyme systems reduces the in viva formation of adducts;
administrat ion of antioxidants has a similar effect. It has been proposed
that the concentration of PAM-DNA adducts in a particular tissue can be
used as a measure of the "effective biologic dose" of a specific PAR. It
should be s imple to determine this dose with currently available sensitive
radioimmunoassay methods. Such methods could be applied to readily
accessible lymphocytes of human populations.
HUMAN EXPOSURE TO AND METABOLISM OF PAHs
.
Humans are exposed to PAHs almost exclusively through the
gastrointestinal and respiratory tracts. Possibly 99t of exposure to
these substances is through the diet. The daily human exposure to PAHs
from air, water, and food has been estimated. Of approximately 1.8-16 fig
of total PAHs ingested or inhaled, 0.2 and 0.02 fig would be derived from
inhalation or ingestion in water, respectively, and the rest from food.
Of the total, approximately 10% would be BaP.
Although the PAHs are ubiquitous in foodstuffs, their content can be
surprisingly high in some foods as a result of pollution from soils,
irrigation waters, atmospheric fallout, and food-processing. The number
of PAHs ingested may be as high as 100, or even higher. Boil ing or
barbecuing substantially affects the composition and quantity of PAHs in
foods .
Occupational exposure to PAHs can lead to inhalation of great
quantities. It has been estimated that a normal adult breathing 20 ma
of air per day can inhale approximately 700 fig of PAHs per day in a work
setting that is rich in PAHs, e.g., coal and pitch-coking plants,
gasworks, and roof-tarring operations. It has also been estimated that
people who remain in tunnels with heavy motor traffic all day can inhale
BaP that would be equivalent to that found in a pack of "old-style"
cigarettes. In accordance with the occupational exposure, cancer
mortality among men employed in coal-tar industries reflects excess cancer
in one or more s ;tes, particularly those involving the lungs.
The manner by which PAHs gain access to the systemic circulation is
not known. Serum lipoproteins may constitute a substantial circulatory
pool of the PAHs, which can be transferred into cells by a non-receptor
mediated process. The pharmacokinetics of PAHs other than BaP in humans
are not well understood.
Normal and malignant human tissues have the metabolic capacity to
biotransEorm PAHs, especially BaP. The individual variation in this
capacity is very large in the human and appears to be genetically
determined. Although it has been proposed that aryl hydrocarbon
hydroxylase activity in lymphocytes and monocytes of lung-cancer patients
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Hi;
is highly inducible, compared with that in "normal" patients, this
relationship has not been definitively established and deserves further
study.
There is little information to implicate diet-derived PAHs in any form
of clinical pathology, despite the relatively large amounts of these
compounds ingested. The gastrointestinal system, including the liver, may
be relatively "resistant" to the PAHs; the nature of such resistance
should be explored.
POPULATIONS OF HYPERSENSITIVE PERSONS
The exposure of cells or animals to pollutants, including PAHs, can
lead to toxicoses, mutagenesis, carcinogenesis, and teratogenesis.
Susceptibility to PAH-induced effects may be controlled at the level of
uptake into specific cells, metabolic activation or inactivation, DNA
repair, expression of DNA damage and its progression to the phenotype of a
mutant cell, and immunocompetence of the person. Several of these steps
(perhaps all) are subject to genetic regulation, although information in
this regard is sketchy. Natural variations in capacity for human DNA
repair lead to increased susceptibility to cancer in some instances, but
the role of the PAHs in this development is not established. Genetically
controlled variations in immunocompetence are observed in people with high
susceptibility to carcinogenesis; no definitve role of the PAHs has been
suggested. The physical state of a PAR and the nutritional or
developmental state of the host contribute substantially to the observed
biologic effect.
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9
RECOMMENDATIONS
MOBILE SOURCES
Several of the polycyclic aromatic hydrocarbons (PAHs) found in
emission from heavy-duty diesel vehicles and other vehicles are
potentially hazardous to human health. On the basis of what is currently
known, research should be conducted to discover practical and economical
adjustments in engine design for reducing particulate and gaseous PAH
emission. In vitro mutagenesis tests could be used to determine the types
of adjustments that influence the concentrations of PAH chemicals active
in these short-term tests. On preliminary testing, the nitro-PAHs have
been mutagenic; thus, they are an important subgroup of the PAHs
purportedly found in mobile-source emission. However, it is not clear
whether these compounds are formed in exhaust or are artifacts of
sampling; more information is needed to clarify this issue.
ATMOSPHERE
_
Data from core sampling of bottom sediments in rivers and bays show
long-range transport of presumably unreacted PAHs. PAH chemistry of urban
and industrial emission plumes should be systematically studied both
regionally and on a continental scale.
It is recommended that monitoring of wet and dry PAH deposition be
included in existing ambient-air quality monitoring networks. The
heterogeneous photooxidation and reactions of PAH with ozone and oxides of
nitrogen should be examined under experimental conditions with emphasis on
the nature and size distribution of carrier particles on both PAH and
reaction products; the findings should be correlated with findings on what
actually occurs in the ambient air.
A system for monitoring in large residential localities should be
encouraged, to determine the concentrations of PAHs emitted from
residential fireplaces, wood-burning stoves, and coal-fired heating
systems and the contributions from these sources relative to those from
industrial and commercial boilers and rural municipal waste-burning units.
Concurrently with the monitoring studies, research should be conducted
on design of equipment, technologies, or methods for controlling PAH
emission from residential fireplaces and wood- and coal-burning stoves.
Extracts of the condensates of smoke and other gaseous emission from wood,
coal, diesel and spark-ignition engines , and tobacco must continue to be
tested in in vitro mutagenicity systems, so that activity profiles can be
established and specific active PAHs identified. There is a need to
develop double checks on the findings of research on extracts of
condensates, to eliminate the uncertainty regarding artifacts that occur
in the sampling or extraction processes. The mutagenicity and
it. a .
carcinogenicity of each active PAR (especially nitro-PAHs and sulfur-
containing PAHs) should be determined in several animal-model systems to
guide the assessment of their contribution to human disease.
EXPERIMENTAL-ANIMAL STUDIES
.
Some data on cocarcinogenic activity of PAHs with other chemicals are
available, but this data base needs to be strengthened, and PAHs other
than benzotaipyrene (BaP) need to be studied further. Specifically, data
are needed to establish whether various PAHs exhibit cocarcinogenic
activity with other components of exhaust from mobile sources or emission
from other combustion sources, especially wood smoke. The potential
promoting activity of PAHs (including BaP) needs to be established. A
model for promotion other than the mouse skin tumorigenesis system is
needed. Of special interest would be a promotion system using human cells.
Extrapolation of findings from animal studies to humans is tentative
without additional biochemical and pharmacokinetic data. Sorting out the
toxic chemicals in any complex mixture (such as automobile exhaust, wood
smoke, or cigarette smoke) is always difficult. Animal models and
compound-specific testing systems are needed to ascertain the toxic
effects (if any) of long-term (chronic) exposure of animals to diesel
exhaust and other complex kinds of emission. In this regard, it is
important to stress that the animal model systems include introduction of
the PAHs (alone, in mixtures, and bound to particles) into the diets of
animals in lifetime studies of carcinogenesis. Such dietary exposure is
based on the data that indicate that ingestion contributes heavily to the
body burden of the PAHs. As results from these studies begin to
distinguish the toxic components, biochemical and pharmacokinetic data on
experimental primates (e.g., squirrel monkeys) will be particularly useful
in confirming the findings in animal species and extrapolating to humans.
With improving characterization of the toxic components, studies should be
conducted on lung deposition, uptake, and clearance of PAHs. Studies on
the relationships of carrier-particle size, surface properties in the
submicrometer range, and absorption and adsorption of individual PAHs
should be continued and expanded with an eye to learning the source of the
greatest exposure to the toxic chemicals.
Preliminary studies in animal models should be conducted as soon as
possible to determine the relationship of PAH exposure to birth defects
and other genetic anomalies. Specifically, it would be important to know
whether chronic exposure of newborns to various types of exhaust and smoke
and to mixtures of PAHs and individual PAHs (present in high concentra-
tions in exhaust) affects development of the central nervous system.
DNA ADOUCTS, ENZYME INnucERs AND REPAIR
What is the relationship of the enzymes and their activity to the
metabolism of PAHs 5 other than BaP, and to the formation of PAM-DNA
adducts and their repair? A broader question is: What are the
consequences of the various DNA adducts known to be formed?
9-2
To answer these questions,
developed for detecting PAH me
antibod ies . Such as says would
metabolite-DNA adduct formatio ~ , r ~ 0 -~~ ~ ~
such as the lung, after in vivo experimental exposure to PAHs, especially
low-dose, long-term exposure. With appropriately designed cell-model
systems that use various cell types, the relationship of in vivo repair of
PAH metabolite-DNA adducts should be examined and an activity profile
developed for the individual known active PAHs. Animals other than mice
and rats should be used to examine PAH metabolite-DNA adduct formation and
the mechanisms by which phenolic antioxidants and inducers of aryl
hydrocarbon hydroxylase (AHH) inhibit the formation of adducts.
more sensitive and specific assays must be
tabolite-DNA adducts, e.g., with monoclonal
be used to determine rates of PAH
n in individual cell tvoes and in organs
Can the PAH metabolite-DNA systems be quantified and further developed
for use in monitoring exposure to specific PAHs? The feasibility of using
adducts as a measure of effective biologic dose should be studied for
low-dose extrapolation of bioassay findings to dose-response curves that
show the rate of adduct formation and its relationship to PAH-induced
neoplasia in animal-model systems. The importance of the findings will
depend on a careful analysis of the background concentrations of PAM-DNA
adducts in tissues--i.e., "noise."
HUMAN STUD IE S
Obviously, all health-related research findings are useful in
improving the protection of human health. Although research that uses
human beings directly poses difficult problems,.there are various kinds of
human studies that avoid those problems. For instance, human tissues can
be used to study the relationship of specific biotransformations of PAHs
to findings of carcinogenicity in animals.
To determine the PAH dose absorbed from human lung tissue, there is a
need to know-the chemical form and binding of PAHs on particles, particle
size, composition, clearance rates, and ultimate fate of inhaled
particle-adsorbed PAHs. These findings would be essential in studying the
relationship of formation of PAR metabolite-DNA adducts and the incidences
of adverse health effects found in animal studies.
Progress in understanding research findings could be greatly improved
if an "inventory" of PAHs identified and measured in normal and diseased
human tissues could be developed. Perhaps samples of appropriate tissues
could be analyzed specifically for this purpose, and biologic and
historical information on the donors could be accumulated. The tissue
profiles of PAH metabolite-DNA adducts or other indicators could be
compared with those derived from environmental sampling or air monitoring.
The findings ;n this report show that a high fraction of human
exposure to PAHs is attributable to dietary intake. The possible
relationship of ingested PAHs to increased incidences of gastrointestinal
(or other) malignancies should be included in epidemiologic analyses.
Such analyses should attempt to Isolate the portion of the prevailing
gastrointestinal malignancy rate in selected populations that is due to
food-derived exposure to PAHs. It is apparent that there is resistance in
the gastrointestinal system to the carcinogenic potential of the PAHs.
The mechanisms responsible for this resistance might involve a great
variety of body systems; no specific body function can be pinpointed.
However, some effort should be directed toward finding these mechanisms.
There can be few clinical parallels to this combination of (1) sustained
impingement of carcinogenic compounds on a system of tissues and (2) so
little evidence of realization of the potential deleterious effects of
such chemicals as the PAHs.
The following studies are suggested for the further development and
evaluation of models for assessing the carcinogenicity relationships in
humans or cell cultures derived from humans.
~ Consider the use of radiolabeled tracers or immunologic methods to
study the metabolism of select PAHs, such as benzotaipyrene, in humans.
The absolute amounts of compound required for single-dose exposure would
be insignificant, compared with the heavy daily exposure commonly found in
foods, but the medical and scientific value of the data obtained would be
very large indeed.
_
· Examine the metabolism, pl~armacokinetics, and DNA binding of
nitro-PAHs .
o Conduct systematic studies of the patterns of tissue enzymatic
activities relevant to PAH metabolism as a function of age, sex, hormone
activities, nutritional state, or state of health (disease).
O Correlate enzymatic activities, especially those involved in PAH
activation to ultimate carcinogens, in one tissue type with the same
biochemical properties of other tissues in the same person. These data
would have the great advantage of eliminating the factor of genetic
diversity in assessing the pathophysiologic significance of such enzymatic
characteristics.
· Determine which genetically controlled deficiencies in immuno-
competence are related to specific immune dysfunctions.
~ Develop better methods for determining the numbers of heterozygotes
at any given Locus and use these methods specifically in populations
exposed to high concentrations of PAHs.
· On the basis of such data, monitor the development of DNA adducts
in humans with the hope of extrapolating to cancer risk.
· Reassess the role of genetically mediated differences in AHH --
responsiveness in determining cancer susceptibility by using multiple
human tissues and multiple enzyme end points (assay for PAH receptors in
human tissue; assay for total and specific cytochrome P-450s by mono-
cLononal antibodies; assay for AHH expression of these genes; use of
lymphoid, epidermal, and fibrobLastic cells as sources of tissues for
enzymatic assays; and use of multiple functional assays for AHH, e.g.,
fluorimetry, high-performance liquid chromatography, and UNA binding and
repair).
~ Determine whether the promotion-associated steps that occur in
mouse skin also occur in human skin. Attempt to develop assays to measure
for "promotability" among humans; i.e., are there genetic variants among
humans for "promotability"?
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