Pesticides, lead and solvents: pregnancy outcome and fertility

1
Pesticides, lead and solvents pregnancy outcome
and fertility

• Markku Sallmén
• Finnish Institute of Occupational Health

2
Pesticides

• The most extensively used group of toxic
  chemicals
• ca. 600 different active ingradients
• about 50,000 various formulations
• simultaneous exposure to different chemicals
  typical
• pesticide formulations may contain solvents

3
Pesticide exposure in farming

• Most of the exposure occurs via the skin
• Some pesticides degrade on the leaves into more
  toxic compounds with even stronger penetration
  capacity
• Inhalation during applications
• Mixing, formulation, spraying, handling of
  treated plants, cleaning of equipment and
  clothes, storage

4
Pesticides

• Comparison between studies difficult
• Different pesticides are used for different
  purposes and in different areas
• Exposure levels vary considerably the highest
  exposures occur in developing countries in poorly
  controlled circumstances
• What is the affected gender?

5
Pesticides shown adverse effects on
spermatogenesis

• DBCP
• 2,4-D (2,4-dichlorophenoxy acetic acid)
• ethylene dibromide
• chlordecone
• carbaryl

6
Pesticides and semen quality

• Study Outcome
• Larsen et al 1998 (longitudinal study) multiple
  outcomes
• Larsen et al 1999 (organic/traditional) multiple
  outcomes
• Padungtod et al 1999 (factory workers) aneuploid
  y
• Tielemans et al 1999 (inf clinic
  clients) () combined quality
• Juhler et al 1999 (dietary pesticides) dead
  spermat.
• Oliva et al 2001 (infertility clinic
  clients) multiple outcomes
• Abell et al 2000 (greenhouse workers) concent./m
  orphol
• Wong et al 2003 (population based) oligozoosperm
  ia
• Dalvie et al 2003 (DDT, malaria control)
  multiple outcomes
• Swan et al 2003 (population based) summary of
  many
• Sanchez-Pena et al 2004 (organophos.) sperm
  chromatin
• reduced semen quality, () suggestive
  association
• no association

7
Pesticides and male fecundability

• Study Association
• de Cock et al 1994
• Larsen et al 1998 -
• Thonneau et al 1999 -
• Curtis et al 1999 (), gender?
• Petrelli et al 2001
• Sallmén et al 2003 ()
• reduced fecundability, () suggestive
  association

8
Male pesticide exposure and couples undergoing
IVF treatment (Tielemans et al 1999, 2000)

• Reduced fertilization capacity
• OR for confirmed exposure 0.38 (0.19-0.78)
• OR for potential exposure 0.54 (0.29-0.99)
• Improved implantation rate
• OR for high/moderate exposure 3.31 (1.25-8.80)
• OR for high(strict) exposure 1.57
  (0.33-7.44)
• Summary effect?

9
Male pesticide exposure and spontaneous abortion

• Savitz et al 1994, reviewed 14 studies
• elevated RR in gt1 study YES
• RR gt 1.5 YES
• Evidence from high
• quality studies NO
• Thereafter mainly US studies have shown
  associations with spontaneous abortion

10
Male pesticide exposure and congenital
malformations

• García 1998, a review on occupational exposure
  and congenital malformations
• 17 studies
• 4 studies showed an association
• Conclusion Inadequate evidence for either
  establishing a relationship between pesticides
  exposure in humans and birth defects or for
  rejecting it.

11
Male pesticide exposure and congenital
malformations

• Pesticide applicators in the Red River Valley of
  Minnesota (Garry et al, 1996, 2002)
• 1996 a register-based study
• - excess in birth defects
• - seasonal pattern
• 2002 a cross-sectional interview study
• - rate of birth defects 7.6 (spring) vs. 3.7
  other season
• - herbicides risk of birth defects
• - fungisides determination of sex of the child
• Salazar-Garcia et al 2004 (DDT) OR 3.4 (1.2-9.5)

12
Conclusion Male pesticide exposure

• High exposure associated with reduced semen
  quality
• Inconsistent findings on fecundability
• Small number of TTP studies
• The findings of the new studies seem to have
  added the evidence that male (or parental)
  exposure to pesticides is associated with adverse
  pregnancy outcome

13
Pesticides and female fertility

• Study Association
• Fuortes et al 1997
• Greenlee et al 2003
• Curtis et al 1999 (6 of 13 pesticides)
• Abell et al 2000
• reduced fertility

14
SummaryFemale pesticide exposure and
fecundability

• There is evidence that female high exposure to
  pesticides is associated with reduced
  fecundability
• This conclusion is based on small number of
  studies, however

15
Female pesticide exposure and adverse pregnancy
outcome

• Nurminen 1995, and Garcia 1998 reviews
• Conclusion the epidemiologic evidence is
  inconclusive as regards the risk of adverse
  pregnancy outcome
• Conclusion Inadequate evidence for either
  establishing a relationship between pesticides
  exposure in humans and birth defects or for
  rejecting it.

16
Female exposure to specific pesticides and
spontaneous abortion

• Exposure/Study Association (OR)
• Hexachlorobenzene (serum, ng/ml)
• Jarrell et al 1998 lt1 1.6 p0.113
• gt1 4.1 p0.02
• DDT serum p,p'-DDE measured
• Korrick et al 2001 (each ng/g) 1.13 1.02-1.26
• Longnecker et al 2003 (per 60 µg/L)
• 1.4 1.1-1.6

17
Pesticides and congenital malformations or foetal
death

• Female Exposure assessment
• Pastore et al 1997 (popul based
  case-control) female occup exp
• Bell et al 2001 (popul based case-control) resid
  ence/application
• Longnecker et al 2002 (popul based
  case-c) () p,p'-DDE
• Ribas-Fito et al 2003 (birth cohort,
  neurodev.) p,p'-DDE
• Medina-Carrilo et al 2002 (popul based
  case-c) female occup exp
• Bell et al 2001 (fetal death, popul
  case-cohort) () residence/application
• Male
• Garcia et al 1998 (case-referent) interview,
  experts
• Garry et al 2002 (cross-sectional, popul
  based) spring vs. other
• Regidor et al 2004 (population based) season
• Either gender
• Kristensen et al 1997(cohort ) agricultural
  census
• Schreinemachers 2003 (population b.) ecologic
• increased risk, () suggestive association

18
Pesticides conclusion females

• Several studies with varying outcomes,
  pesticides, level of exposure, affected gender,
  and quality of the study
• High exposure seems to be associated with
  increased risk
• Exposure should be restricted through efficient
  protection
• Should pregnant be transferred?

19
Lead Pregnancy outcome and fertility
20
Simultaneous exposure to several metals

• Studies around Rönnskär copper smelter
• excess of spontaneous abortion, and stillbirths
  in pregnancies of wives of men exposed to lead,
  copper, zinc, gold, silver, cadmium, mercury,
  arsenic, and sulfur dioxide
• carry-home exposure to the wives remains a
  possible alternative explanation

21
Population-based studies

• Rachootin and Olsen 1983
• case couples examined or treated for a problem of
  infertility at Odense University Hospital
• questionnaire information on job and exposure
• female exposure to lead, mercury, and cadmium
  were associated with infertility

22
Maternal lead exposure and spontaneous abortion

• B-Pb µmol/L OR 95 CI
• A retrospective study among biologically
  monitored workers
• Taskinen 1988 0.5-3.1 0.8 0.5-1.4
• Measured within a year of pregnancy
• gt1.4 1.9 0.4-9.4
• A prospective study (B-Pb measured at gestational
  age 4-12 w)
• Borja-Aburto 0.24-0.48 2.3 --
• et al. 1999 0.49-0.72 5.4 --
• gt 0.72 12.2 --

23
Maternal lead exposure and fecundability

• Sallmén et al 1995 (study among women
  biologically monitored for exposure to lead)
• Blood lead FDR 95 CI
• not exposed 1.00 reference
• lt0.5 µmol/l 0.93 0.56-1.57
• 0.5-0.9 µmol/l 0.84 0.45-1.45
• 1.0-2.4 µmol/l 0.80 0.42-1.54
• Eight most heavily exposed subjects
• 1.4-2.4 µmol/l 0.53 0.19-1.52

24
Maternal lead exposure and cognitive development
prospective studies

• Study Mean Blood Lead Effect
• Boston 7.37 µg/dl
• Cincinnati 4.6 ---gt14.1
• Cleveland 5.8 ---gt 6.5 -
• Port Pirie 14.4-gt21.2-gt17.6
• Sydney 9.1-gt8.1-gt12.5 -
• Yugoslavia 14.4---gt24.3 (/-)
• 1 µmol/L 20.7 µg/dL

25
Lead and semen quality

• Apostoli et al 1997 (a review)
• Exposure to lead at blood lead 1.9 µmol/L (40
  µg/dL) is hazardous for male reproductive
  function
• reduced sperm count, volume, and density
• changed sperm motility and morphology
• a modest effect on endocrine profile is possible
• Viskum et al 1999
• The effect is, at least partially, reversible

26
Studies on birth rates and male exposure to lead

• Study PbB level Effect
• Selevan et al. 1984 1.2 µmol/l
• Coste et al. 1991 1.9 µmol/l -
• Gennart et al. 1992 2.2 µmol/l
• Lin et al. 1996
• duration of exp. gt5 years, 2.4 µmol/l
• Bonde and Kolstad 1997 1.8 µmol/l -
• reduced fertility, - no effect

27
Relative risk (RR) of infertility and male
exposure to lead Sallmén et al 2000

• Estimated PbB RR 95 C.I.
• µmol/L
• 0.5-0.9 1.27 1.08-1.51
• 1.0-1.4 1.35 1.12-1.63
• 1.5-1.9 1.37 1.08-1.72
• 2.0-2.4 1.50 1.08-2.02
• gt 2.5 1.90 1.30-2.59

28
(No Transcript)
29
Male lead exposure and spontaneous abortion

• Study PbB µmol/L OR 95 CI Selevan 1984
  1.2 - 1.9 1.5 0.8-3.0
• 2.0 - 2.9 1.1 0.6-1.9
• gt 3.0 0.9 0.3-2.3
• Al-Hakkak 1986 1.8 - 4.6 3.0 plt.01
• Lindbohm 1991 1.0 - 1.4 1.0 0.6-1.7
• 1.5 - 1.8 1.3 0.5-3.4
• gt 1.9 1.6 0.6-4.0
• Alexander 1996 1.2 - 1.8 1.0 0.6-1.7
• gt 1.9 0.7 0.4-1.5

30
Male lead exposure and congenital malformations
or perinatal death

• Study PbB µmol/L OR 95 CI
• M
• Sallmén 1992 gt 1.0 2.4 0.9-6.5
• P
• Kristensen 1993 exposed 2.4 1.2-4.9
• P/M
• Alexander 1996 1.2 - 1.8 2.9 0.6-13
• gt 1.9 2.5 0.5-11
• Mmalformation study
• Pperinatal death study

31
Solvents pregnancy outcome and fertility

• From a presentation of
• Dr. Marja-Liisa Lindbohm
• Finnish Institute of Occupational Health

32
Organic solvents

• important occupational reproductive hazards
• widely used in various fields of industry
• volatile liquids
• absorbed via inhalation and through the skin
• most solvents traverse the placenta
• diverse group of compounds

33
Reproductive effects of solvents

• in several human studies exposure related to
• reduced fertility
• spontaneous abortions
• birth defects
• low birth weight
• in some studies exposure related also to
• menstrual disorders and change in hormone levels
• pregnancy-induced hypertension
• neurobehavioral performance
• reduced semen quality
• childhood cancer

34
Maternal exposure to solvents in some occupations
and spontaneous abortion
35
Cumulative percentage of pregnancies by maternal
exposure to solvents (Sallmén et al 1995)
36
Industries and individual solvents related to
reduced fertility or adverse pregnancy outcome

• Dry cleaning tetrachloroethylene
• Semiconductor industry ethylene glycol ethers
• Shoe and leather industry aliphatic
  hydrocarbons, toluene, hexane
• Laboratory work toluene, xylene, chloroform

37
Ethylene glycol ethers

• used in paints, dyes, lacquers, waxes etc.
• Methoxyethanol
• embryotoxic and teratogenic in mice and rats
• teratogenic effects seen at doses that do not
  cause overt maternal toxicity
• Ethoxyethanol
• induced skeletal defects in rats, multiple
  defects in rabbits (inhalation exposure)
• in rats, impaired performance in behavioral tests

38
Spontaneous abortion, fertility and maternal
exposure to mixtures containing ethylene glycol
ethers in semiconductor industry (Correa et al.
1996, Chen et al 2002)

• Outcome Exposure RR/FR 95 CI
• Spontaneous abortion
• low 1.0 0.6 1.7
• Correa et al medium 1.4 0.8 2.6
• high 2.8 1.4 5.6
• Time-to-pregnancy
• Correa et al medium 0.8 0.6 1.1
• high 0.7 0.4 1.1
• Chen et al Exposed 0.59 0.37 0.94

39
Conclusions Effects of solvent exposure on the
reproductive health of women

• High exposure to solvents increases the risk of
  spontaneous abortion and decreases fertility
• The findings on birth defects less conclusive,
  but suggesting adverse effects
• Particular solvents associated with adverse
  effects ethylene glycol ethers,
  tetrachloroethylene, toluene

40
Exposure assessment and recommendation

• Assessment of solvent exposure with industrial
  hygienic measurements or biological monitoring
• In some countries the guidelines recommend that
  solvent exposure should not exceed 10 of the
  threshold limit value during pregnancy
• Reproductive effects have been used as the basis
  for some TLVs

41
Exposure to solvents and semen quality or hormone
levels

• Solvents reduced sperm quality and decreased
  implantation rate
• Ethylene glycol ethers and 2-bromopropane
  reduced sperm count
• Styrene and acetone sperm anomalies
• Toluene and solvents in general decrease of
  hormone levels

42
Solvent exposure and seminal characteristics in
225 men who had their first infertility
consultation (Oliva et al 2001)
Seminal charateristic OR 95 CI
Seminal volume gt3.8 ml 2.4 0.8 7.6
Sperm concentration lt1x106/ml 2.7 0.9 8.3
Sperm output lt3x106 2.5 0.8 7.9
Sperm motility lt50 3.1 1 9.5
Sperm morphology lt30 3.0 1.0 9.0
43
Cumulative percentage of pregnancies by paternal
exposure to solvents (Sallmén et al. 1998)
44
Ethylene glycol ethers and male fertility
45
Paternal exposure to solvents and spontaneous
abortion
46
Paternal solvent exposure and pregnancy outcome

• Inconsistent findings on the effects of exposure
  on low birth weight
• An excess of birth defects in the children of
  male painters, but not in the children of other
  exposed workers
• Some evidence for childhood leukemia or nervous
  system cancers, and paternal exposure to solvents
• Evidence inconclusive, although suggestive
  associations noted

47
Conclusions Effects of solvent exposure on the
reproductive health of men

• Solvent exposure related to reduced sperm quality
• Ethylene glycol ethers harmful for male
  reproductive system
• Carbon disulfide related to decreased libido and
  potency in men
• No clear association between solvent exposure and
  decreased fertility

48
Male pesticide exposure and spontaneous abortion

• Study Association (OR)
• Arbuckle et al 1999, Ontario Farm Family Study,
  phenoxy herbicides
• lt20 weeks of gestation 1.1 0.6-1.9
• lt12 weeks of gestation 2.5 1.0-6.4
• husband not using protective 5.0 0.7-36.2
• equipment
• Petrelli et al 2000 3.8 1.2-12.0
• Crisostomo et al 2002 6.2 1.4-27.9
• Salazar-Garcia et al 2004 (DDT)1.5 1.1-2.1

49
Male/female pesticide exposure and spontaneous
abortion

• Arbuckle et al 2001
• Ontario farm population
• Timing of exposure / affected gender
• preconceptional early (lt12 weeks) abortions
• (male exposure?)
• postconceptional late (12-19 weeks) abortions
• (female exposure?)

50
Male pesticide exposure and spontaneous abortion

• Pesticide applicators in the Red River Valley of
  Minnesota (Garry et al, 2002)
• Fungicides 1.6-2 -fold increase in risk for
  miscarriage/fetal loss
• Herbicides increased risk in first-trimester
  miscarriage
• The overall toxicity data suggest a male-mediated
  event
• Also, women engaged in pesticide application were
  at risk

51
Female pesticide exposure and spontaneous abortion

• Study Association
• Bell et al 2001 pesticides showed no strong
  association with fetal death
• (ORs from 0.9 to 1.4)
• Exposed lived in 1 8 adjacent sq miles from
• the application

52
Parental pesticide exposure and congenital
malformations

• Kristensen et al 1997 a study among Norwegian
  farmers
• Exposure to pesticides associated with
• spina bifida
• hydrocephaly
• limb reduction
• cryptorchidism
• hypospadias

53
Fecundability Density Ratio (FDR) of Pregnancies
by Fathers Exposure to Lead Sallmén et al 2000

• Estimated PbB µmol/l N FDR 95 C.I.

0.5-0.9 203 0.92 0.73 - 1.16 1.0-1.4
79 0.89 0.66 - 1.20 1.5-1.8 21
0.58 0.33 - 0.96 gt 1.9 23
0.83 0.50 - 1.32 gt 1.5 (combined)
44 0.70 0.47 - 1.01
54
Reproductive effects of some solvents in animal
tests

• ethoxyethanol teratogenic and spermatotoxic
  effects
• methyl alcohol teratogenic effects
• methyl ethyl ketone decreased fetal body weight
• n-hexane testicular lesions
• xylene and white spirit (prenatal exposure)
  learning and memory defects

55
Maternal exposure to solvents and pregnancy
outcome a meta-analysis(McMartin et al. 1998)

• 559 articles identified around epid. studies 90
• Spontaneous abortions
• five studies included (n2899)
• summary OR1.25 (95 CI 0.99 1.58)
• Birth defects
• five studies included (n7036)
• summary OR1.64 (95 CI 1.16 2.30)
• Reasons used for the exclusion of (several
  potentially important) studies criticized

56
Tetrachloroethylene

• used as a dry cleaning agent and degreaser
• passes across the placenta
• animal studies
• no clear teratogenic effects
• signs of fetotoxicity observed in some studies
• a two-generation study found decrease in litter
  size and postnatal survival at 300 ppm
• propably carcinogenic to humans (2A, IARC)

57
Maternal exposure to tetrachloroethylene in dry
cleaning and spontaneous abortion
58
Toluene

• used in paints, inks, coatings, adhesives, and in
  the leather, rubber and graphic industries
• low birth weight, microcephaly and facial
  abnormalities in children of women abusing
  toluene by inhalation during pregnancy
• reduced birth weight in prenatally exposed rat
  pups
• effects on cognitive function reported in rats
  after prenatal exposure

59
Maternal exposure to toluene and spontaneous
abortion or reduced fertility
Population Relative risk 95 CI
Spontaneous abortions OR
Pharmaceutical factory w. 1.9 0.6 6.4
Laboratory workers 4.7 1.4 15.9
Monitored workers 1.4 0.4 4.9
Audio speaker factory w. 2.8 1.3 5.9
Reduced fertility (ttp) FDR
Monitored workers 0.71 0.40-1.26
Printing industry workers 0.47 0.29-0.77
60
Maternal exposure to solvents and oral clefts
61
Methodological issues in epidemiologic studies on
solvents

• response rates satisfactory in most studies
• confounding usually, but not always controlled
  for
• outcome data mainly from the medical records
• data on exposure usually based on workers own
  reports - underreporting ?
• in some studies exposure assessed by experts
• exposure to mixture of solvents common
• small sample size in studies on birth defects and
  individual solvents

62
Reproductive endocrine effects in women with
fuel/solvent exposure (Reutman et al 2002)

• Outcome urinary endocrine markers related to
  nonconceptive menstrual cycles (N63)
• Exposure assessment levels of aliphatic and
  aromatic hydrocarbons (HCs) in exhaled breath
• Result preovulatory luteinizing hormone level
  significantly lower among women who had higher
  internal doses of aliphatic HCs
• Conclusion compounds in fuel and some solvents
  may act as reproductive endocrine disruptors

63
Genetic susceptibility to benzene and shortened
gestation (Wang et al 2000)

• Aim examine whether the association between
  exposure and outcome is modified by two
  susceptibility genes CYP1A1 and GSTT1 responsible
  for detoxification of solvents (542 mothers)
• Results
• benzene exposure associated with a decrease in
  mean gestational age
• when stratified by the maternal CYP1A1 genotype,
  the decrease was significantly greater for the AA
  group than for the AA/aa group
• Provide evidence of gene-environment interaction

64
Carbon disulfide exposure and the prevalence of
sexual complaints
65
Solvent exposure and count of motile sperm
(Cherry et al 2001)

• A case-referent study of 656 infertility patients
• Aim to examine whether cases with low motile
  sperm count (lt12x106ml) were more likely than
  referents to have had exposure to solvents
• Exposure assessment job exposure matrix of
  previous studies on solvent exposure
• Results
• OR 2.1 (95 CI 1.2-3.4) for moderate exposure
• OR 3.8 (95 CI 1.4-10.6) for high exposure