Perspectives

in Pathology

Human Health Effects of Agrichemical Use

DENNIS D. WEISENBURGER,
The

use of pesticides

grown dramatically

fertilizers

in agriculture

over the past SO years. Currently.

600 active pesticide

data are available
mental exposure

and nitrogen

MD

ingredients

are used. but adequate

for only approximately

(paraquat),

of humans to agrichemicals

(insecticides,
chemical

hemoglobinemia
have been
reproductive

cancers.

efforts

sures wherever

possible.

pesticides,

particularly

abnormalities

and adverse

effects due to pesticides

to control

Research

classes.

or eliminate

also is needed

health. HUM PATHOL

24:571-576.

Copyright

inwit

psticicle
ar~tl

tisc

fidd

CIOJS

boo1\

on

this

5Lthjcc.t

do not

Therefore.

HUMAN

human expoto better

acterize and quantitate the adverse effects of agrichemicals

LVithout
~mducc

also have

with pesticides

to only a few chemical

are needed

damage

and infant met-

A variety of cancers also

The health effects associated

to be restricted

enhanced

Immunologic

ptxditc1s.
of. fresh

dt-OJ In 30;
(0 50%.
, However, rhe Iwnefits
of
1xsticiclc
ti.46 iilitsl tw (xmsiclet-etl
in light of itic.reaGtig
cx)ticetm
rega-cling
etr~irotitiietilal
degratl;itiot~,
bx~tkc3~
safety, and public hcatth. In this article I h;tvc attempted
IO stittttii3t~i~e the c~ut~rrtit level of ktiowlcclge
t~egartlitig
lhe tiL~tirati health
cftrcts
of +yic~hetiiical
LISC, with
tiiLich
of the infi)t-tiiatioti
taken fixm cxirt-etit rc\ ieu3 mtl
;I

and results

lung

of~tSt-ic,tilttit-;tl
1m)cluctiott

w011ld

acute and chronic

fumigants).

to various

and developmental

been reported.
appear

to exposure

;igticLtltLri~al

toxicologic

is common

ammonia),

(nitrate in groundwater).

linked

hematopoietic

fungicides,

burns (anhydrous

tiuttiber

100 of these. Environ-

in both acute and chronic health effects, including

neurotoxicity

has

approximately

EXPOSURE

TO AGRICHEMICALS

char-

In thr

on human

(8 1993 by W.B. Saun-

f~irtnet-s,

ders Cornpan!

lion

Iltiitrd

three

l~rttl

Stales

ttiillioti

fmiily

ap1m~xitiiatel)

hired

fatm

rttetnl~el-s

;Lgt-ichettiicats.

Itt

ttiatiLL~L~tLti~iti~

mtl

haw

ndditioti,

worker-s.
potenti;it

Jx33otis

f.ortnLtl;Ltioti

of

two

tiiillioti

arid

six

tnit-

contact

with

etiiJ>loved
agrichcttiicals,

itt

the

;Ls

well

x5 other

plant gt-o\vcta and tlal\cstt~rs, aeri~tl applic~itol-s,

tiitttigatot3,
pix~f5siotial
gtx~utid md
strtictutxl
q@calors,
md their wfqx)rt
~~etw~titiel. xc
likely to havr
a Agtiific at11 esposut-cto ~tfitichcttiic,als. l~tit~ittg~~esticiclc
application
most txJ~osLit~e
is via tletm;il
alxxq~tioti.
III
L\;olIcet3 who Alt o~~LlJ~;lliotl;Ll~~
rsJoStYl
to olyytlophJsph;it~
ittscc-lic~itles.
otw
cxi
cstitmlt.
ttw
biologic
csposut-e
In tiw;isut~itig iwl htocd cell 01 1ktsiiia cholitivstetxsc
twrls Iwlow and after the a1,1Aic;ttioti. Iti such
sicticlies ap1~to~itii~i~eI\ 2OCT to -kOi; of fkiti q~1Aic:itors
IMVC ;i sigtiificmt
twluctioti
in their JAastii;i
chotitresIrixc

Icvel,

vvcii

tiighrr

woi-ket-s,
\VOI~ld

sotti<

with

Iicton
fal~tll

lah

pationat
espo5tit~~s.
sure for the gettci-;Ll
iti xicl

AI

of

wJx)r-trd

atttt

toxicit\.
iti

where;is

ttiigratit

f~oi~ti~ulatot-s.

and

1;Lrtii
thirtl-

)ltlb. +-

Jx~piilatioti

Jx3ticidca

are

wotkm

IVotio~c~LtJ~atio~i~~t
geticral

s\mtptcwis

Jxmxmtages

pesticide

txJx~sLtix3

~Lttiotig

rhe

;tppe;ii- to tw low t-clati\e

(0 occii.-\ major s0111x~
of 1wsticide es1x)Jx)Jmlatiott

~11~0L1tid the

rrsults
liotw

ftx)tn

, sit1c.e

the

LISC of.

qm~xittiatel\

L~trittd Stales houscholcls

use pchticidrs.
fti
Aotic~ , dti estitttateti
30 tiiillioti kilograms
of
\vcw 5oIcl fi)t. home aid gartleti usr in 19X0.
I:txmt 197ti 10 1977 the Ett~~ii~c~titiietit~tt Irotec3ioii
.~gvtlcy cst itmled
that ~s1~ositre
I0 1x3tic.icleh itt atitl
;tt~outtd the tiotttc reauttecl in 2.5 ttiiltioti re[x)tTcd sytiif)Iotii;itic. iticidetils.
Of p~it~ticrtlar ~otice~ti ;irc pestiLides
t bar 1xrsihl iti tlic home rti~irotiitiettt
fi)r long peiiodh
01 titttc. fxit-tic~tttat~t~ t~rtiiiticittt5
such
;I
c~litotxlatir.
Houe
tlttst atttl I;IWI~ residurs
wt
thottgll~ to tqtmcttt
ittt1)ortmt
meal\
ofcspoaurr
tot- stttall chilhett.
Howcvcr, little i:, ktiowti tqatxlittg
the c1trotiic, health efkts
01 Iow-lr\vl
tioti~c txf~o4tir~~h.

!HM

of

(hlili)rtiia
1xhcicks
____--__

571

HUMAN PATHOLOGY

Volume 24, No. 6 (June 1993)

Contrary to widespread public belief, pesticide residues in fresh and processed foods are typically absent
or well below the legal tolerance levels. However, in
rural areas contamination
of drinking water by pesticides
and nitrates from fertilizers is a concern, since water is
a major part of the diet and significant exposures ma)
occur over a lifetime.H However. few scientific studies
of the health effects of such exposures have been done
and little is known.

ACUTE HEALTH

EFFECTS

OF AGRICHEMICALS

Due to lack of a national database, no accurate or

current statistics are available regarding the incidence
of acute pesticide poisoning in the United States. Approximately
20,000
persons are taken to emergent)
rooms each year for actual or suspected pesticide poisoning, and approximately
10% are admitted to the hospital. Each year 30 to 40 persons die of acute pesticide
poisoning in the LJnited States.
In California,
where
pesticide poisoning is a reportable
illness, there were
approximately
17,000 hunian pesticicle exposure incidents in 1!)87, approximately 30% IO CO% of which were
symptomatic.
Of these, only 1,507 cases were occupational, with 744 cases demonstrating
systemic toxic
symptoms.!
However. many affected workers probabl)
never see a doctor and therefore
go undiagnosed
anti
unreported.
Occupational
deaths in California over the
past 10 years have averaged about one per year.! In
contrast, acute pesticide poisoning is thought to be a
major global health problem.
with approximately
25
million occupational poisonings per year. Most of these
occur in third-world countries,
where pesticide education and monitoring
and the use of safety equipment
are largely nonexistent.
In the United States most cases of occupational
acute pesticide poisoning
result in neurotoxicity
and
are due to exposure to organophosphate
or carbamate
insecticides.
Organochlorine
insecticides also are neurotoxic, but are no longer commonly used in the United
States. Some of the acute and subacute neurotoxic
effects of the organophosphate
insecticides are listed in
Table 1. Their principle toxic effect is the inhibition of
cholinesterases
in the blood and nervous system. which
prevents degradation
of acetylcholine
at the neuronal
synapses and results in overactivity of the cholinergic
neurons. The carbamates
and organochlorine
insecticides can cause a similar picture of acute intoxication.] l.l and these effects are usually reversible.
However, a delayed,
progressive,
and irreversible
distal
polyneuropathy
may occur as a result of organophosphate exposure and is due to Wallerian degeneration
in large myelinated nerve fibers that leads to axonal
death. In contrast, the pyrethroid insecticides induce
only cutaneous paresthesias, which last 12 to 18 hours.
The herbicides are generally not thought to be neurotoxic in humans, although a variety of fungicides and
fumigants may cause acute and chronic neurotoxic
effects.
Paraquat is a contact herbicide that causes severe
and progressive
lung damage resulting in anoxia and
572

death. The initial phase of lung damage is an extensive

alveolitis with neutrophil
infiltration
and progressive
pulmonary
edema. The second phase follows shortly
thereafter
and consists of rapidly progressive
and extensive intraalveolar
and interalveolar
fibrosis, which
destroys the alveolar architecture.
Plcute renal failure
due to tubular necrosis and liver dysfunction
also ma)
be seen in paraquat poisoning.
Anhydrous ammonia is a colorless gas that is used
as a fertilizer. It is usually handled as a pressurized liquid
for ease of tr-anspoI-tation and storage. Because of high
pressure and a temperature
of -28F,
a stream of vaporizing anhyclrorls ammonia will penetrate and freeze
any tissue that it strikes, resulting in chemical burns of
the skin and q13.
Inhalation of the gas will result in
Iaryngospasm,
tracheitis,
bronchitis.
and chemical
pneumonitis with pulmonary edema. Eye injury may result in permanent damage. &hereas lung injury is usually
reversible.
An acute health effect of groundwater
contamination by nitrate is the occurrence
of methemoglol~ir~emia. either clinical or subclinical,
in infants under ti
months of age. The current drinking water standard
for nitrate-nitrogen
of 10 ppm was set pritnarily to prevent this occurrence.
However, cases of infant methemo&)binemia,
some
resulting
in death, continue to oc<,
cur in rural areas.

CHRONIC HEALTH
AGRICHEMICALS
Neurologic

EFFECTS

OF

Effects

It has become increasingly

apparent from recent
studies that acute and chronic occupational
exposure
to a variety of pesticides can result in mild to severe
deterioration
in neurologic
function that may he irreversible. Chronic neurologic
effects have been associated with exposures to the organophosphate,
organochlorine, and carbamate insecticides, as well as a variety
of fungicides (tnercurials, diphenyl. hexachlorobenLene,
hexachlorophene)
and fumigants (methyl bromide, carbon disulfide, sulfuryl fluoride). .i-L A list of commonly
reported chronic neurologic etiects is given in Table 2.
In a recent case-control epidemiologic
study Rosenstock
et al found convincing
evidence of chronic central
nervous system effects in workers with a history of a11
episode of acute organophosphate
insecticide
intoxication. These investigators
found that the poisoned
group did significantly less well than the control group

HUMAN HEALTH EFFECTS

OF AGRICHEMICAL

on (:ancer recently concluded that 43F oLa wide variet\

of pesticides they reviewed Fverc or probably Fvere carcinogenic in hunlans.ST Uith pesticides (if all the various
tvpes showing some evidence of carcinogenicit)in these
studies, the concern about human cxposure seems to
be well tounded.
With regard to mechanisms
of carcinogenesis, a survey of the genotoxic ;ic.tivities 01.6% pesticides by Garrett et al found that 35 of the pesticides
(51%) tested positive, including
org.:~nc~f~llospl~ate and
thiocarhamate
insecticides,
pyrethroid
insecticides.
and
a variety of herbicides
and fungicidcas. Howevtar. some
nongenotoxic
pesticides also ma\ he involved in carcinogenesis via their epigenetic propel,tics. such as tumor
promotion,
ilihibition
of intercellular
c.ommuriicatic,n.
or induction
of peroxisome
prolifer,.it ic)n.
Much of the epidemiologic
data available on the
carcinogenicity
of pesticides come fro111 studies of pcr~11s employed
in agricultural
or related occupations.
Although
farmers have a lower 0veralX mortality
f01
cancer in general, consistent
excesses for certain types
of cancer (Table 3) suggest a role for \~ork-related f;~c.tars. The escesses of lip and skin (ancer are thought
10 be due to ultraviolet
light. Note that the risks fog
most of the other cancers are relativelv low, in the range
of 1.5fold to threefold, although su(.ii >tudies are like11
to underestimate
the true risk. Although farmers typic.ally perform man! tasks resulting
in a variety of VSposures, pesticides have received the nlost attention.
However, few studies have attempted
to assess the c;mWI risks of exposure to specific pesticidts,.
Table 4 shows
the cancers that have been associated with occupational
exposures
to specific pesticides
OI
(lasws of pestic~itles.~ The epidemiologic
data linking specific pesticide exposures
to hematopoietic
cmcer
tie, nonHodgkins lymphoma, leukemia, and multiple mycloma)
are the strongest, whereas the data on soft tissur sarcoma
arc mixed and for Hodgkins
disease it is weak.-
However, t!vo recent studies have strr~~gtl~encd the association between soft tissue sarcoma and exposure to
thr phenoxyacetic
acid and chloropllenol
pesticides..
Little is know1 ahout specific pesticides and ( ancer of
the brain. although ovarian (.arcinonw
has bcten associated wifh exposure
to trixine
hrrhic-ides
in OIIC

in tests assessing a wide array of neuropsychologic

functions. including
auditory attention,
visual memory, visuomotor
speed, sequencing
and problem solving, and
motor steadiness,
reaction,
and dexterity.
Rosenstock
et al concluded
that even single episodes of clinicall)
significant acute organophosphate
intoxication
may be
associated with a persistent decline in neuropsvchologic
function.
A characteristic
feature of carbon disulfide poisonirig is the presence of a parkinsonian-like
svndronle.i
Interestingly,
recent epidemiologic
studies of Parkinsons disease have found that rural living, exposures to
pesticides, and drinking well water are associated with
the disease.. However, further studies are needed to
clarify these relationships.
Also of note is the report by
Sterman and [arma that as many as 19% of individuals
exposed to well water containing
a carbamate insecticide
(aldicarb) had neurologic
complaints,
inchtding
parestllesias, locomotor difficulties, visual problems, and di/7iness.
Carcinogenic

USE (Dennis D. Weisenburger)

Effects

111 recent years there has been increasing

public
concern that exposure to pesticides may pose a potentially serious cancer risk to the general population.
Currentlv, the available data are insufficient
to estimate a
pesticide-related
cancer rate for the general population,
but it must be small when compared with other factors,
such as smoking. However, excesses of certain types of
cancer, particularly
those of the hematopoietic
system.
have been observed in occupational
groups with significant pesticide exposures.L)5-i! These findings should not
be surprising
since a variety of pesticides are known to
cause cancer in laboratory
animals, even though many
older pesticides have not been adequately tested.7,! In
a recent survey of 37 pesticides evaluated for carcinogenicity b) the National Toxicology
Program,
Hoovel
and Blair found that six pesticides (13%) were positive
in both sexes in mice and rats, 10 pesticides (2 I %) were
positive in both sexes of one species, and six pesticides
(13%) were positive in one sex of at least one species.
For six other pesticides (13%) there was inadequate
01
equivocal evidence for carcinogenicity,
whereas 19 pesticides (40%) tested negative. The 16 chemicals that were
positive in both sexes of at least one species included
organochlorine
and organophosphate
insecticides,
herbicides, fungicides,
and fumigants,
suggesting
that no
chemical class of pesticides can be considered
problem
free. Similarly. the International
Agency for Research

TABLE 3.

573

High-Risk Cancers in Mortality Surveys

of Farmers
~~_.__~

HUMAN PATHOLOGV

TABLE 4.

Types of Cancer Associated

Pesticide Exposures

Volume 24, No. 6 (June 1993)

With Specific

study.

Recent case-control
studies in Kansas and
Nebraska have demonstrated
a significantly
increased
risk of non-Hodgkins
lymphoma (risk ratios, 1.3 to 2.2)
among farmers using the phenox)zcetic
acid herbicide
,4-D, with the risks increasing
threefold to sevenfold
among those reporting
use fin 21 or more clays per
year. The use of organophosphate
insecticides
by Nebraska farmers also resulted in a significant P.q-fold increased risk for non-Hodgkins
lymphoma. independent
of the effects of 2,4-D, with the risk being over threefold
for those using these insecticides
21 or II~OIT clays pe1
year. Recently, a case-control
study of canine nonHodgkins lymphoma revealed a positive association (risk
ratio, 1.3) with the dog owners use of 2,&D, with the
risk rising to a twofold excess with four or more year])
lawn applications. Although mutagenesis
tests and animal experiments
provide only weak support for the role
1 l-D has been shown to have
of ,A-D as a carcinogen,
_,
multiple epigenetic properties,
acting both as an inhihitor of intercellular
comIlillnication
and a stimulator of
peroxisonie
prolifel-ation.~
Leukemia and brain cancer in children have been
associated with parental employment
in agriculture
and
lymexposure to pesticides,. c as has non-Hodgkins
phoma in recent, yet unpublished,
studies. Brain cancel
in children and stomach cancer in adults also have
been linked to N-nitroso compounds,
which could result
from drinking groundwater
contaminated
by nitrate.x
Increased rates of non-Hodgkins
lymphoma also have
been found in communities
and counties where nitrate
contamination
of groundwater
is a problem. .4lthough
nitrate per se does not appear to present a cancer risk,
it acts as a precursor to nitrite which forms via bacterial
reduction in saliva. Nitrite then reacts tvith other nitrosatable dietary substrates in an acid-catalyzed
reaction
in the stomach to produce N-nitroso compounds,
which
are potent carcinogens
in experimental
animals. It is
intriguing
that several of the cancers associated with
farming (non-Hodgkins
lymphoma. multiple myeloma.
brain cancer, and stomach carcinoma)
are reportedly
increasing in several countries around the world.~*
Immunologic

Effects

Ample and convincing

evidence that pesticides OI
pesticide contaminants
can modulate
or alter the im574

mmle response in experimental

animals has been reported, but there is little evidence to suggest that pesticide exposures
compromise
human health through
interference
with the immmne system. However, contact dermatitis
due to pesticides appears to be more
common
than preciously
thought,
and asthma-type
reactions can be triggered by pesticide exposures.
Although altered inlm~lnoglobulin
and complement
levels
and changes in T-cell populations
have been reported
in humans exposed to pesticides,
no adverse health
effects ha\:e been noted. However. impaired neutrophil
chemotaxis
accompanied
by an increase in respirator)
tract infecGons ~vas correlated
with the length of occupational
exposure to organophosphate
pesticides in
one study.! Further studies of the immune effects of
pesticides in humans are needed since depressed
immmnity is known to predispose
humans to a varietv of
cancers, including non-Hodgkins
ly~~~phoma.
Pulmonary Effects
Chronic respiratory
impairment
has been found in
workers with many years of exposure to organochlorine
a11d organophosl~hate
insecticides.
Persistent pulmonary fibrosis has been reported in survivors of paraquat
poisoning, ;md chronic cough, bronchiolitis
ohliterans,
and bronchiectasis
have been described as sequelae of
anhvdrous
ammonia exposure.
Reproductive

Effects

For Iiiany pesticides

the animal data necessar) to
evaluate potential reproductive
toxicity are not available
and, when animal data are available, even minimal human data are lacking. Agricultural
chemicals, including
the organoc~hlorine
and organophosphate
insecticides,
have been shown to be reproductive
toxicants in female
laboratory
animals, but there have been no reports of
female reproductive
toxicity in humans.
In contrast, the organochlorine
pesticides dibromochlorol~rop~l~le (DBW) and chlordecone
(Depone) are
reproductive
toxicants in the human male. Azoospermia,
oligospermia,
and decreased sperm motilitv have been
reported with DBCP, whereas chlordecone
causes oligospermia and decreased sperm motility. ,4 higher than
expected prevalence
of female births and an increase
in spontaneous
abortiom
in females whose husbands
were exposed to DBCP have been reported.
Ethylene
dibromide exposure also affects the human male reproductive system, resulting
in decreased
sperm counts,
decreased
sperm motilit!~ and viability, and abnormal
morphology,
as IveIl as decreased
fer;ility. Exposure
of males to carbarvl, a carbamate
insecticide,
has been
reported to result in an increased number of abnormal
sperm.; A recent study of male workers exposed to 2,4D also revealed
decreased
sperm counts,
decreased
sperm motility and viability, and abnormal
morphology. Thus, human reproductive
effects due to a variet)
of pesticides have been clearlv demonstrated
in males.
However, large d&t gaps in &r current knowledge of
the reproductive
effects of pesticides are evident and
much additional
research in this area is needed.

HUMAN HEALTH EFFECTS

OF AGRICHEMICAL

Developmental Effects
The extent to which pesticides contribute
to the
incidence
of developmentally
related problems in humans is unknown,
although approximately
50% of the
active pesticide ingredients
that have been tested are
teratogenic
in animals. 55 The final outcome of a developmental
disturbance
can be death, malformations,
growth retardation,
functional disorders, or any of these
manifestations
in combination.
However,
functional
deficit studies are currently
not required for the registration of a pesticide.
Most studies of humans exposed to pesticides have
failed to find an increase in fetal malformations.56.57
However, a study of Vietnam veterans revealed an increase of spina bifida, facial clefts, coloboma of the eye,
and neoplasms
in the first year of life in offspring.58
Studies by the Vietnamese also revealed increases in anencephaly, orofacial defects and clefts, and molar pregnancy in persons exposed to pesticides during the war,
although these latter studies are difficult to evaluate.5
Epidemiologic
studies also have linked a variety of congenital malformations
to the rural setting and pesticide
use, including
limb reduction
defects, musculoskeletal
defects, facial clefts, and cardiac and urogenital
defects.60-62 Perinatal
pesticide exposure
in humans has
been reported to cause chronic neurotoxicity,
including
cerebral palsy. Recently, an increase in abortions,
infant prematurity,
and congenital malformations
was detected in female floriculture
workers exposed to pesticides.j3 These findings suggest that extensive evaluation
and quantitation
of human exposure levels and the developmental
consequences
of such exposures
are
needed. Future epidemiologic
studies should concentrate on pregnant
women at high risk for exposure to
pesticides,
particularly
those involved in agricultural
work.
CONCLUSION
Experimental
and epidemiologic
investigations
indicate that pesticides can cause a variety of adverse acute
and chronic health effects in humans and that these
effects are not restricted to only a few chemical classes,
Therefore,
enhanced
efforts are needed to control and
eliminate human pesticide exposures whenever possible.
Additional
research is needed in all of the above-mentioned areas to better characterize
and quantitate
the
adverse health effects of agrichemicals
in humans. In
particular,
future studies should concentrate
on those
individuals at high risk for specific pesticide exposures,
such as farm workers and commercial
applicators.
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1991
3. Spigiel RW, Gourley DR, Holcslaw TL, et al: Organophosphate
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575

USE (Dennis D. Weisenburger)

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1986
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1990
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