Transcript Chemical Teratogenesis

Organ toxicity
•
Blood supply
•
Presence of specific enzyme or
biochemical pathway
•
Function / position
•
Vulnerability to disruption / ability to
repair
Pulmonary Toxicity
Influences:
• Receives 100% of right heart output
• Internal milieu in greatest contact with
environment
Pulmonary Toxicity
Influences:
• Receives 100% of right heart output
• Internal milieu in greatest contact with environment
• Designed to absorb and excrete gases
• Major area for absorption and excretion of volatiles
• Design encourages contact with aerosols and
micro-particles
• Defended by mucus and cilia against particles
• Defended by mucus against aerosols and volatiles
Pulmonary toxicity
Types of Toxic Lung Injury:
• Irritation to airways by water-soluble
gases
– e.g. ammonia, chlorine
• Mucosal injury (water insoluble
compounds)
– e.g. petroleum, ozone, NO2 phosgene
• Pulmonary fibrosis
– mediated by macrophage uptake
e.g. silica, asbestos
• Stimulation of an Allergic Response
– toxins react with airway proteins to
form antigenic complexes
e.g. toluene di-isocyanate dusts
• Carcinogenesis
– cigarette smoke, asbestos, polycyclic
aromatic hydrocarbons
Neurotoxicity
cell damage
– neuronopathy (trimethyltin)
– axonopathy (hexane)
– myelinopathy (hexachlorophene)
neurotransmission interference
• receptor blockade
–(organophosphates)
• ion channel blockade
–(tetrodotoxin)
–ciguatera
Neurotoxicity
Influences:
Protective
• CNS protection by blood-brain
barrier
• Little internal metabolism of
potential toxins
Vulnerable
• Complex system
• Poor regenerative ability
Renal toxicity
Influences:
•
Kidneys receive 25 % of cardiac output
• Huge reserve capacity:
– hence potential delay in recognising
toxicity
• Toxicity enhanced by tubular concentration
– e.g. gentamycin, cephaloridine
• Some protection from prior detoxication by liver
Renal toxicity
Types:
•
Ischaemia
– eg NSAIDS (prostaglandin synthetase
inhibition)
• Tubular injury
– cadmium, gentamycin, cephaloridine,
lead
• Glomerular injury
– cadmium
• Crystalluria
– oxalate, sulphonamides
• Allergic interstitial nephritis
–
penicillin, cephalosporins, sulphonamides
Renal Toxicity
Assessment / Detection
Urine components
– cells
– proteins (tubular or glomerular)
– small molecules normally fully absorbed (amino
acids)
– H+, Na+, K+, water
Urine volume flow
• Plasma components normally cleared
–
urea, creatinine, H+, phosphate
• Dynamic function tests
– inulin, CR-EDTA, creatinine clearances
Hepatic Toxicity
Hepatic Structure
Hepatic Structure
Hepatic Toxicity
Types of injury:
• necrosis
• fat accumulation (steatosis)
• cirrhosis
• cholestasis
• carcinogenesis
Metabolism by Liver
• drug or other foreign substance
• reactive metabolite
• conjugate or oxidise
• excretion
Metabolism by Liver
P450 enzymes in the liver
Hepatic Metabolism of Paracetamol
(Acetaminophen) to Toxic Reactive
Metabolite NABQI
NABQI
Poisoning occurs when
• the quantity of paracetamol ingested exceeds the
capacity of the high affinity glucuronidation and
sulphation pathways, and
• the flow through the P450 route uses up the liver’s
stock of glutathione.
NABQI is thus free to react with the next most
‘convenient’ substances, like protein and lipid.
Hepatic Toxicity
Evaluation:
• Measurement of plasma
enzyme
activities
– aminotransferases (AST ALT) alk
phos, yGT
• Hepatic functional performance
– albumin, coagulation factors,
bilirubin, lactate
• Histology
Hepatic Toxicity
Cholestasis:
toxicity to biliary epithelium
• biliary dysfunction
• intra-hepatic cholestasis
• may sometimes have
immunological
basis
– e.g. phenothiazines, some
antibiotics, anabolic steroids,
oestrogens erythromycin
estolate, i.v. lipids
•
–
Chemical Teratogenesis
Teras = monster
• 3 - 7% Human babies born with a malformation
Aetiology
• 65%
Unknown
• 20%
Transmission of known genetic defect
• 5%
Chromosomal abnormality
• 2 - 3% Infection
Toxoplasma, Rubella, Cytomegalovirus,
Herpes (TORCH) and Syphillis
• 4%
Maternal disease (diabetes, nutrition,
addiction)
• 1 - 2% Mechanical (uterine structure, cord wrap)
• 1 - 5% Alcohol, drug abuse
Teratogenesis
Mechanisms
• Mutation
• Chromosomal aberrations
• Mitotic interference
• Nucleic acid metabolism / function alteration
• Energy metabolism interference
• substrate deficiency
• pathway inhibition
• Membrane alterations
Teratogenesis
Characteristics
• Selectivity and Specificity
• Genetic differences
• Susceptibility and development stage
• Manifestations
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death
malformation
growth retardation
functional disorder
Properties of the teratogen
• Access to embryo & fetus
• Dose–response effect
• No effect level (NOEL)
Chemical Teratogenesis
Thalidomide
Critical Periods:
21-22 days: absent external ears, cranial nerve
disorders
24-27 days: phocomelia (especially arms)
27-28 days: phocomelia (especially lower limbs)
34-36 days: hypoplastic thumbs, anorectal
stenosis
• 10,000 infants born worldwide with defects
• Withdrawn 1961, no new cases of these
defects
• Problems of anticipation from animal tests
Chemical Teratogenesis
Fetal Alcohol Syndrome
Severe:
• Microcephaly
• Severe and mental retardation
• Cardiac and renal abnormalities
• Maxillary hypoplasia
• Growth retardation
Mild:
• Growth retardation
• Attention deficits with normal intelligence
Chemical Teratogenesis
Folic Acid Antaganists
e.g. Aminopterin, methotrexate
Critical Time: 8/40 - 10/40 (first 2 months)
High rate of intrauterine death
20 - 30 % of surviving fetuses have
malformations
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hydrocephalus
cleft palate
meningomyelocoele
absence of frontal bones
craniosynostosis
absent digits
rib defects
Note:
Documented effect of (non-toxic origin) mild
folate deficiency on incidence ofspina bifida
Chemical Teratogenesis
• Care in prescription to women
of childbearing age and not
just in pregnancy
• Beware of self-medication /
naturopathic preps
• Beware of drug interactions
with oral contraceptives