Pesticides and Trace Organics

1
Pesticides and Trace Organics
ENS3320Biochemical toxicology

• Introduction
• Pesticides and their toxic effects
• Trace Organics chemicals and their receptors
• Toxic effects and risk Assessment of trace
  organics
• Electronic wastes PBDE
• Concluding remarks

2
1. Introduction
SOURCES OF TRACE ORGANICS
Combustion of organic substances by products
Manufacturing of pollutant chemicals
Bio-magnification in food chains
Daily products Meat (beef and fish), milk, egg.
Agent Orange By-products of chlorine related
chemicals, including pesticides.
Waste incineration, Metal processing, Fossil fuel
combustion (vehicle emission).
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POPs, persistent organic pollutants.
1.3 Introduction

• Lipid soluble, hard to remove, easy to
  accumulate, magnification via food chains with
  high concentrations in tertiary consumers.
• Examples, polychlorinated Aromatic hydrocarbons
  (PAHs), Polycyclic biphenyls (PCBs),
  Dichloro-Diphenyl Trichloroethane (DDT), PBDE
  (Polybrominated Diphenyl Ether), Dioxins (TCDD)
  and furans.
• Environmental estrogens, mimic estrogenic
  compounds in animal body, endocrine disrupters.
• Related to gene mutations and cancer.

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The UNEP 12 POPs
1.4 Introduction

• Pesticides
• Aldrin
• Dieldrin
• Endrin
• Chlordane
• DDT
• Heptachlor
• Mirex
• Toxaphene
• Hexachlorobenzene (HCB)

• Industrial Chemicals
• PCBs (Polychlorinated Biphenyls)
• HCB
• Unwanted By-products
• PCDDs (Poly Chlorinated Dibenzo Dioxins)
• PCDFs (Polychlorinated Dibenzo Furans)
• PCBs
• HCB

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1.5 Introduction
Toxicity Scale of Example Substance
LD50, mg/kg (approximate)
Substance
DEHP (plasticizer), di(2 ethylhexyl)phthalate)

• 100,000
• 10,000
• 1,000
• 100
• 10
• 1
• 0.1
• 0.001
• 0.00001

Practically non toxic, gt 1.5 X 10 4 mg/kg
Ethanol
Sodium Chloride
Slightly toxic, 5 X 10 3 to 1.5 X 10 4 mg/kg
Malathion
Chlordane
Heptachlor
Parathion
Moderate toxic, 500 to 5000 mg/kg
Tetrodotoxin
Dioxin
Very toxic, 50 to 500 mg/kg
Botulinus toxin
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2. Pesticides

• Including herbicides, fungicides, rodenticides
  and substances used to control pests.
• Control intended for preventing, destroying,
  repelling or mitigating any pests
• Usage agricultural pesticides, public health
  pesticides, wood preservatives, anti-fouling
  paints, household products, etc
• Four main types 1 Organochlorine, 2
  organophosphate, 3 carbamate and 4 pyrethroid
  pesticides.

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2.1 Organochlorine pesticide

• Commonly used in the past, but many have been
  removed from the market due to their health and
  environmental effects and their biomagnifiable
  properties (e.g. DDT and chlordane).
• OCs and their metabolites resist degradation by
  chemical, physical or biological means.
• Persistent and have half-live ranging from months
  to years and in some cases decades.
• DDT is the most notorious organochlorine (OC)
  insecticide widely used in agricultural
  production around the world even today.

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General effects of organochlorine pesticides

• toxic to humans and other animals and are highly
  toxic to most aquatic life. They can have serious
  short-term and long-term impacts at low
  concentrations.
• sub-lethal effects such as immune system and
  reproductive damage of some of these pesticides
  may also be significant
• build up in the fatty tissues of humans, plants
  and animals. Most of them are attracted to fatty
  tissues and organs and are accumulated
  significantly through food-chain
  (bio-magnification) and hence large animals in
  high trophic levels accumulate most.

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DDT (Dichloro diphenyl trichloroethane)

• Raised public awareness about the dangers of
  pesticides, with a specific focus on persistent
  OCs and DDT due to the publication of Silent
  Spring by Rachel Carson (1907-1964), leading to
  the establishment of USEPA.
• Banned in many countries in the 1970s in response
  to public concern and mounting scientific
  evidence linking DDT with damage to wildlife.

http//en.wikipedia.org/wiki/Rachel_Carson
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DDT(dichlorodiphenyltrichloroethane)

• Banned in the United States in 1972, but is now
  being used in many countries including China to
  kill mosquitoes to avoid malaria.
• DDT is an organochlorine slowly transformed to
  1,1-dichloro-2,2-bis(p-dichlorodiphenyl)ethylene
  (DDE) and 1,1-dichloro-2,2-bis(p-chlorophenyl)etha
  ne (DDD), and ultimately transformed into
  bis(dichlorodiphenyl) acetic acid (DDA) at a very
  slow rate.
• DDA are readily excreted in urine, but DDE tends
  to bio-concentrate and accumulate in food webs.
• Fish, milk contaminated with DDT or metabolites
  DDE are major sources for human uptake.

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Toxic effects of DDT

• Toxic to many types of aquatic organisms, even at
  low concentrations. It has moderately to slightly
  toxic to studied mammalian species via the oral
  route.
• Chronic effects on the nervous system, liver,
  kidneys, and immune systems in experimental
  animals.
• Adverse effects on the liver, kidney and immune
  system due to DDT exposure have not been
  demonstrated in humans.
• Evidence for mutagenicity and genotoxicity is
  contradictory, but carcinogenicity is equivocal.
• Confirmed to be environmental estrogen.

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Examples of Organochlorine Pesticides
1) DDT DichloroDiphenyllTrichloroethane
2) Endosulfan
3) Methoxychlor
4) Heptachlor
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Methoxychlor (MXC)

• Protect crops, ornamentals, livestock, and pets
  against fleas, mosquitoes, cockroaches, and other
  insects, as a replacement for DDT
• Readily metabolized, non-accumulative
• No acute or chronic effects has been reported on
  human
• Used extensively to protect crops, ornamentals,
  livestock, and pets against fleas, mosquitoes,
  cockroaches, and other insects,
• Xenoestrogen and endocrine disruptor

14
Endosulfan and its toxic effects

• USEPA Category Ib Highly Hazardous
• Beta- (very persistence, half life 800 days)
  and alpha- isomer
• Acutely neuro-toxic to both insects and mammals
  and affects CNS Epilepsy
• Hyperactivity, tremors, convulsions, lack of
  coordination, difficulty breathing, nausea and
  vomiting, diarrhea, lethal effects
• Chronic endocrine disruptor Hypothyroidism
• Environmental estrogen
• Reproductive and developmental toxicity

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2.2 Organophosphate Pesticides

• Most OPs are insecticides.
• Developed during the early 19th century, but
  their effects on insects, which are similar to
  their effects on humans, were discovered in 1932.
• Not persistent in the environment. They degrade
  rapidly by hydrolysis on exposure to sunlight,
  air, and soil.
• An attractive alternative to the persistent
  organochlorine pesticides, such as DDT and aldrin

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General effects of Organophosphate

• Organophosphate pesticides irreversibly
  inactivate acetylcholinesterase, which is
  essential to nerve function in insects, humans,
  and many other animals.
• Many organophosphates, in particular
  Chlorpyrifos, are highly toxic to fish. It is
  necessary to exercise extreme care and caution
  not to contaminate fish bearing water bodies.

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Examples of organophosphate pesticides
Chlorpyrifos
Malathion
Dichlorvos

Parathion
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Malathion CAS121-75-5

• The most commonly used insecticide
• EPA estimates that annual use of it is over 30
  million pounds
• Inhibits a CNS enzyme called acetylcholinesterase
  (AChE)
• Cause over-excitation of synaptic neuron
• Confirmed mutagen, suspected carcinogen
• Other effects immune system, sperm activity and
  hormone system

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2.3 Carbamate Pesticides

• Carbamates are effective insecticides by virtue
  of their ability to inhibit acetylcholinesterase
  (AChE) in the nervous system.
• The carbamylation of the enzyme is unstable, and
  the regeneration of AChE is relatively rapid
  compared with that from a phosphorylated enzyme.
  
• They are less dangerous with regard to human
  exposure than organophosphorus pesticides.

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Examples of Carbamate Pesticides
Aldicarb
Carbofuran
Acute intoxication symptomsdizziness, sweating,
laboured breathing, unconsciousness, vomiting,
pupillary constriction, muscle cramp, excessive
salivation
Carbaryl
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Aldicarb CAS116-06-3

• Control mites, nematodes and aphids by applying
  directly to the soil
• USEPA estimated that 5.2-5.6 million pounds of
  aldicarb were used nationwide
• Reversibly inactivate acetylcholinesterase
• Highly toxic insecticide (more potent than
  malathion)
• Little evidence on mutagenicity / carcinogenicity
• Suppress immune system

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2.4 Pyrethroid Pesticides

• Natural Pyrethrins is a botanical insecticide
  made from Chrysanthemum flowers while Pyrethroids
  such as Cypermethrin and tetramethrin are its
  synthetic chemical analogues.
• Provide rapid knockdown effects on insects but
  with only little residual activity.
• To increase their effectiveness, a synergist -
  Piperonyl butoxide (PBO) is often added to the
  formulations.
• Toxic to fish and other aquatic organisms, they
  must be used carefully so as not to contaminate
  the waterbodies.

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Examples of Pyrethroid Pesticides
Cypermethrin
Tetramethrin
Allethrin
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2.5 Take home exercises

• Make a table to summarize the types of
  chemicals, general properties of pesticides and
  their biological targets.
• Compare and explain the chemical structures and
  toxic targets of OPs and OCs.
• Are carbamates safer than Ops and OCs? Why?

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Polychlorinated aromatic hydrocarbons, PAHs
3. Trace Organics chemicals and their receptors

• Products of tobacco smoke and combustion of
  fossil fuels
• Benzo-a-pyrene as a representative chemical
• They undergo primary (Phase I) and secondary
  (Phase II) detoxification steps and metabolism
• Could become DNA adducts causing DNA damage and
  point mutation
• As chemical carcinogens, leading to mutation of
  oncogenes and cancer.

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Dioxins
3. Trace Organics chemicals and their receptors

• Polychlorinated dibenzo-p-dioxins form a group of
  75 congeners, including the most toxic compound
  TCDD, 2,3,7,8- tetrachloro dibenzo-p-dioxin. EPA
  limit in drinking water is 0.00003 mg/L (ppm).
• FDA limits for seafood 50 ppt.
• Waste water discharge limit 0.5 ppt.
• Air 4-5 ppt or 45 ppt , related to climatic
  conditions.
• US daily intake (estimated) 20 X 10 12 g/kg bw.
  WHO data 1 4 pg/kg/day (tolerable daily
  intake).

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Dibenzo-para-dioxin structure formula and numbers
of chlorinated isomers
3. Trace Organics chemicals and their receptors
No. of chlorines (xy) No. of isomers 1
2 2 10 3 14 4 22 5 14 6 10 7 2 8
1 Total 75
Adapted from IARC et al, 1997
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3. Trace Organics chemicals and their receptors

• A wider group of related compounds considered as
  dioxin-like PCDFs (polychlorinated dibenzo
  furans), PCBs (polychlorinated biphenyls),
  diphenyl ethers, naphthalenes, etc.

1
9
O
3
3
2
2
2
8
4
4

3
7
Cly
Clx
Clx
O
Cly
4
6
5
6
5
6
Polychlorinated dibenzodioxins (PCDDs)
Polychlorinated biphenyls (PCBs)
9
1
2
8
3
7
O
Clx
Cly
4
6
Polychlorinated dibenzofurans (PCDFs)
Benzoapyrene
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3. Trace Organics chemicals and their receptors
1
9
O
Cl
Cl
2
8
7
3
Cl
O
Benzo-a-pyrene
6
Cl
4
TCDD, 2,3,7,8 Tetrachloride Dibenzo Dioxin
NH
3-methylcholanthrene
NH
Indolo3,2-bcarbazole found in plants and diets
CH3
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Characteristics of dioxins
3. Trace Organics chemicals and their receptors

• Low vapor pressure and water solubility lipid
  soluble
• Persistent, chemically stable
• Bio-accumulated in lipid, highly lipophilic
• long half-life (5-10 years in human)
• high affinity on Aryl hydrocarbon receptor (AhR)

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Mechanism of intracellular actions of dioxins and
dioxin-like compounds
3. Trace Organics chemicals and their receptors

n nuclear pore factors
p23
Hsp90
n
dioxin
unoccupied
AHR
Ah receptor
CYP1A1
Hsp90
ER
CYP1A gene induction
n
ARNT
AHR
AAA
AAA
heterodimer
n
AHR
AHR
DRE
ARNT
ARNT
n
Nucleus
Cytosol
CYP 450
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3. Trace Organics chemicals and their receptors
Anti-estrogenic effects of TCDD

• It was found that testosterone (a male hormone)
  levels DECREASED in small numbers of workers
  occupationally exposed to TCDD with serum TCDD
  concentrations of 20 pg/g blood lipid (Egeland et
  al., 1994).
• Speculative of lower sperm counts in European
  countries to be related to higher dioxin levels.
• Lower T4thyroxine binding globulin ratio and
  plasma thyroid stimulating hormone levels related
  to high PCDD and TEQ.

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Estrogen Receptors
3. Trace Organics chemicals and their receptors

• Environmental estrogens stir debate.
• Would chemical compounds being modified in living
  organisms become estrogen receptors mimics?
• Would those chemical compounds, when accumulated,
  cause deficiency in reproductive system in making
  estrogenic effects in males (lower sperm count)
  or lower the estrogenicity in females (reduced
  egg production)?
• Evidence found in mice, marine organisms and
  fish. How about human beings? Ans Not fully
  understood.

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Proved Xenoestrogen
3. Trace Organics chemicals and their receptors

• Chlorinated organic compounds, e.g. Atrazine,
  Chlordane, DDT, Endosulfan, Methoxychlor, PCBs.
• Plastics, e.g. Bisphenol A, nonylphenol (plastic
  softener).
• Pharmaceuticals, e.g. Cimetidine (dopamine
  receptor blocker for ulcer treatment), synthetic
  estrogens (for birth control).
• Aromatic hydrocarbons (from vehicle exhaust).

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3. Trace Organics chemicals and their receptors
Environmental Estrogens!?
Estrogens
PCBs
36
3. Trace Organics chemicals and their receptors
Adapted from Kuiper et al., 1998. Sci. Med.
5(4)36-45.
37
3. Trace Organics chemicals and their receptors
Inactive Receptor
Active Receptor
Estrogens
Anti-estrogens
Hormone Binding Region
DNA Binding Region
Other estrogenic compound
Target Gene
38
Adapted from Kuiper et al., 1998. Sci. Med.
5(4)36-45.
Tamoxifen a partial anti-estrogen in use as a
breast cancer therapeutic
3. Trace Organics chemicals and their receptors
39
Environmental estrogens are able to bind to
estrogen receptors as mimic to enhance or reduce
(anti-estrogenic) the activation of target genes.
ERs forming homo- (aa or ßß) heterodimers (aß)
Other estrogenic compound
Target Gene
Estrogen, e.g. 17ß estradiol.
3. Trace Organics chemicals and their receptors
40
Compound A
Receptor for A
e.g. AhR
metabolised to B-like compound
Inhibits?
Enhance ?
Receptor for B
e.g. ER
Compound B
Q Compare and contrast the structure and
function of ER and AhR. Explain why some dioxin
and PCBs are ligands of AhR, but could also be
considered as an environmental estrogens.
41
Adapted from Matthews et al., 2005. Aryl
hydrocarbon receptor-mediated transcription
ligand- dependent recruitment of estrogen
receptor a to 2,3,7,8-tetrachlorodibenzo-p-dioxin-
responsive promoters. Mol. Cell. Biol.
255317-5328.
Adapted from Ruegg et al., 2008. The
transcription factor aryl hydrocarbon receptor
nuclear translocator functions as an estrogen
ß-selective co-activator, and its recruitment to
alternative pathways mediates anti-estrogenic
effects of dioxin. Mol. Endocrinol. 22304-316.
42
4. Toxic effects and risk Assessment of trace
organics

• Dioxin has different toxicities on animals.
• Sub-lethal effects are of major concern.
• What mechanism of dioxins would take to cause
  their toxic effects?
• How dioxins affect cell at the molecular level?
• What component of cell can recognize dioxins?
• It the most toxic compound known to human, what
  can we do to assess our risk to this compound?

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Acute Toxicity of TCDD species specificities
4. Toxic effects and risk Assessment of trace
organics
Adapted from Tschirley et, 1986
44
DIOXINS Chloracne
4. Toxic effects and risk Assessment of trace
organics

• 1899, chloracne
• Agent orange used in Vietnam war
• Users and victims suffered from chloracne
• PCBs and dioxins caused chloracne
• Mechanisms not known, believed to be related to
  the halogens.
• Causing dilations of the infundibular or
  suprafollicular area of the hair follicle with
  hyperkeratinization (accumulation of keratin and
  sebaceous gland secretion)

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4. Toxic effects and risk Assessment of trace
organics
Chloracne is an occupational dermatosis with
numerous acne form lesions located on the face
and neck behind the ear.
Follicular Hyperkeratosis mouse skin treated
with tetrachlorobiphenyl (Puhvel et al., 1982)
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4. Toxic effects and risk Assessment of trace
organics
Ukraine President Yushchenko was suffering from a
Dioxin intoxication during his election, high
concentration of TCDD (100,000 picograms (10-12
µg) per L (so 100 ppb)) was found in his blood,
normal person could only have a few ppt.
photo taken on July 6 (left) and Dec 10, 2004
showed his face with symptoms of chloracne.
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Other Dioxin Contamination Accidents Happened
Worldwide
4. Toxic effects and risk Assessment of trace
organics

• 1962-1970 Agent Orange used in Vietnam war
• 1968 Yusho, Japan
• 1976 Accident in Seveso, Italy
• 1979 Yucheng, Taiwan

Adapted from Schecter et al, 1999
48
The Yucheng(??) Incident
4. Toxic effects and risk Assessment of trace
organics
Adapted from Guo, Yu, Hsu Rogan, 1999.
Environmental Health Perspective 107715-719.

• Background
• Central Taiwan in 1979, dioxins and PCBs mixture
  were used in rice oil processing.
• About 2,000 people were found to be contaminated
  and mass poisoning occurred.
• Symptoms included chloracne, hyperpigmentation,
  and peripheral neuropathy, and the illness was
  referred to as Yucheng(??).
• Yucheng cohort were estimated to have consumed
  about 1g of PCBs and 3.8 mg of PCDFs during that
  time!
• They were interviewed and their clinical symptoms
  had been detected since then.
• Women have higher prevalence of anemia, headache,
  goiter, gum pigmentation, chloracne.

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Prevalence () of reported diseases ever
diagnosed by a physician in Yucheng and control
groups in Taiwan, 1993
4. Toxic effects and risk Assessment of trace
organics
Adapted from Guo, Yu, Hsu Rogan, 1999.
Environmental Health Perspective 107715-719.
50
Basic Concepts of Toxic Equivalency Factor (TEF)
4. Toxic effects and risk Assessment of trace
organics

• dioxin-like compounds exist in environmental and
  biological sample as complex mixtures of
  congeners.
• compare toxicology of various dioxin-like
  compound.
• simplify risk assessment and regulatory control.
• Toxic Equivalency Factor (TEF) of 2,3,7,8-TCDD is
  1
• Combine PCB and dioxins together 4 x 10 12 g
  TEQ per kg bw. (TEQ Toxic Equivalency Quotient)

51
4. Toxic effects and risk Assessment of trace
organics
Adapted from Van den Berg et al, 1998
52
4. Toxic effects and risk Assessment of trace
organics

• TEQ (PCDDi TEFi) (PCDFi TEFi) (PCBi
  TEFi)

• The criteria for including a compound in the TEF
  scheme for dioxin-like compounds
• Show a structural relationship to the PCDDs and
  PCDFs
• Bind to the Ah receptor (Ah R)
• Elicit Ah R-mediated biochemical and toxic
  responses
• Be persistent and accumulate in the food chain

Adapted from WHO et al, 1998
53
4. Toxic effects and risk Assessment of trace
organics
PCDD/PCDF levels in the general population
1980-1991
Adapted from Schecter, A (ed). 1994. Dioxins and
Health. Plenum Press, New York, 710p.
54
4. Toxic effects and risk Assessment of trace
organics
Estimated Dietary Intake of PCDDs and PCDFs in
the UK.
55
4. Toxic effects and risk Assessment of trace
organics
Estimated Dietary Intake of PCDDs and PCDFs for
Canadian Adults as Calculated by Birmingham et al.
Adapted from Schecter, A (ed). 1994. Dioxins and
Health. Plenum Press, New York, 710p.
56
Problems with I-TEF
4. Toxic effects and risk Assessment of trace
organics

• Tolerable Daily Intake (TDI) of 1 to 4 pg I-TEQ
  per kg body weight per day has been established
  for dioxins by the World Health Organization
  (WHO). The upper limit of 4 is provisional and
  the ultimate goal is to reduce human intake
  levels below 1 pg I-TEQ per kg body weight per
  day.
• The TEF concept remains the most feasible
  approach for risk assessment purposes.
• Pharmacokinetic differences between species
  (human mouse?) can significantly influence the
  TEF value.
• Unknown additive or non-additive interactions
  might hamper the derivation of consensus TEF
  values.

57
PCBs
4. Toxic effects and risk Assessment of trace
organics 4
Clx
Cly

• PCBs are known to cause birth defects,
  neurological damage and thyroid imbalances. Their
  use was banned in the U.S. in 1976.
• Would people at risk consuming the contaminated
  health food products?
• PCBs contain 209 congeners with varying harmful
  effects.
• RfDose for Aroclor 1016 is 0.00007 mg/kg/day
• PCB is a class B2 carcinogen, the ED10 is 50
  mg/kg/day

58
Effects of PCBs
4. Toxic effects and risk Assessment of trace
organics

• Some PCBs are also AhR agonists with much lower
  TEF except PCB126 (3,3,4,4,5-pentaCB is 0.1)
  and PCB129 (3,3,4,4,5,5-hexaCB is 0.01).
• They induce CYP enzymes (2A1 and 2B1).
• They enter the cell freely to alter calcium ion
  signaling in lymphocytes, neurons and muscle.
• They produce immuno-modulatory effects, and the
  development of cardiovascular disease.
• Some are even estrogenic and some are
  anti-estrogenic effects.

59
5. Electronic wastes PBDEs and metal ions

• Directive Of The European Parliament And Of The
  Council On The RESTRICTION OF THE USE OF CERTAIN
  HAZARDOUS SUBSTANCES IN ELECTRICAL AND ELECTRONIC
  EQUIPMENT-(Amended by 2005/618/EC, 2005/717/EC,
  and 2005/747/EC) The six hazardous substances
  being banned are the heavy metals lead, cadmium,
  mercury and hexavalent chromium, as well as two
  groups of brominated flame retardants -
  polybrominated biphenyls (PBB) and polybrominated
  diphenyl ethers (PBDE).
• Scientists link depressed immune systems and
  fewer cubs to PCB contamination of polar bears.
  PBDEs - suspected of having same toxic effects as
  PCBs. Penta bromo diphenyl ether (pentaBDE) is
  found in sewage sludge spread in US.

60
5. Electronic wastes PBDEs and metal ions
Adapted from Hooper and McDonald (2000) The
PBDEs An Emerging Environmental Challenge and
Another Reason for Breast-Milk Monitoring
Programs. Environ. Health Perspect. 108 387-392.
61
5. Electronic wastes PBDEs and metal ions
Structures of PBDEs
BDE47 2,2,4,4 BDE99 2,2,4,4, 5 BDE153
2,2,4,4, 5,5
PBDEs
O
(X Y 10)
Brx
Bry
I
Thyroxine
I
CH2CH(NH2) COOH
O
HO
I
I
The chemical structure of BDEs also resembles
thyroxine, a thyroid hormone. Initial studies
indicate that BDEs could interfere with the
metabolism of thyroid hormones, and with their
transport throughout the body.
62

5. Electronic wastes PBDEs and metal ions
Bioaccumulation of PBDEs

• PBDE levels in breast milk of North American
  women have increased from two to 200 parts per
  billion over the last decade and 300-400 times in
  Canadian lake trout from 1978 to 1998.
• One of the major concerns about BDEs in breast
  milk is the exposure of infants, they may have
  neurological effects and affect IQs of new born
  babies.
• Developmental exposure to brominated diphenyl
  ethers results in thyroid hormone disruption in
  rats (Zhou et al., 2002 Hallgren and Darnerud,
  2002).

63
Toxic effects of PBDEs
5. Electronic wastes PBDEs and metal ions

• Serum T4 levels (thyroxine) reduced, but EROD
  (ethoxy-resorufin-O-deethylase) and UDPGT
  (uridine diphosphate glucuronosyl transferase)
  levels higher in exposed group.
• T4 glucuronidation by phase II UDPGT in liver
  might be one of the mechanisms for lower T4 in
  blood, causing hypothyroidism.
• Hypothyroxinemia during fetal or postnatal
  periods occur even when T3 (triiodothyronine) is
  normal, causing permanent functional
  abnormalities and mental retardation in children.

64
6. Concluding Remarks

• Persistent Organic Pollutants (mainly from
  foodstuffs, e.g. fish) cause chronic effects on
  human as hormone disrupters, can affect our
  immune system, and may even be carcinogenic.
• Tight regulations have been imposed on them but
  some dangerous pesticides, including DDTs, and
  still being used in developing countries.
• Due to the binding to AhR and power to induce
  CYP1A, TEF values have been assigned to dioxin
  and dioxin-like compounds. Using TEQ values, we
  can better manage the risk of these POPs.
• PBDE is found in e-waste, it could affect our
  thyroid hormone system and may have significant
  impacts on growth and developments in infants.