Metals
More toxic as soluble ionic form or organometallics.
Increased absorption, accumulation in tissues; slow excretion
- Toxic responses involve:
- many organs i.e. CNS, liver, kidney, cardiovascular & reproductive systems, G.I. tract & skin
- route-specific e.g. Ni dust – inhaled (lung cancer), swallowed (liver damage) or on skin (allergies)
- many are carcinogenic e.g. Ni, Cd (genotoxic activation-independent inorganic carcinogens)
Reactive Oxygen Species & Protective Pathways
Transition Metals (Fe, Cu) catalyse Fenton Reaction.
Protective pathways: SOD, superoxide dismutase; CAT, catalase; GSH Px, glutathione peroxidase
Pesticides
Generally have acute & chronic effects on nervous system
* Toxic heavy metals and metalloids (e.g. lead arsenate) were widely-used in early mass agriculture – now replaced by Organochlorine pesticides
Organochlorine pesticides
DDT, dieldrin
- very lipophilic & persistent
- some are immunotoxic & carcinogenic (promoters)
- tend to bioaccumulate & bioconcentrate in the foodweb
Organophosphates (OP) & carbamate esters
inhibit acetylcholinesterase (AchE) on neuronal post-synaptic clefts (“aged AchE”)
- Many need metabolism by cytochrome P450 (CYP) to active forms eg.(malathion malaoxon)
Pyrethroids
based on natural pyrethrins
least persistent pesticides (but can cause neurological disturbances)
Neonicotinoids
- stable hydrophilic systemic pesticides*; uptake & transport to all plant tissues (different to surface contact pesticides)
- selective for invertebrate CNS (less toxic to birds & mammals, but toxic to beneficial insects, e.g. bees; low dose stim., high dose paralyses)
Aromatic hydrocarbons
Produced in many industrial processes
(adhesives, detergents, polymers, pesticides, cigarette smoke & fuel)
Many “endocrine disruptors” causing hormonal disruption
Polyhalogenated aromatic hydrocarbons (HAHs)
- Fat soluble and persistent
- Have numerous toxic effects including:
carcino- & terato- genicity; hepato-, neuro- & immuno- toxicity; potent tumour promoters - Includes:
fire retardants/heat exchangers
polychlorinated biphenyls ‘PCBs’
polybrominated biphenyls ‘PBBs’
hexachlorobenzene
eg. Furans, Dioxins
Polycyclic aromatic hydrocarbons (PAHs)
- Formed from incomplete combustion of organic matter
- Ubiquitous environmental contaminants
- Some are potent carcinogens and immuno-suppressants
- PAHs & HAHs bind the aromatic hydrocarbon (Ah) receptor
- specifically inducing CYP1A enzymes to enhance toxicities of other xenobiotics (by increasing metabolic activation)
Most carcinogenic PAHs must first be converted to reactive metabolites
Acute adverse effects of solvents
interfere with nerve function.
Used in confined spaces causes acute CNS-depressive effects:
Disorientation, euphoria, giddiness, confusion, progressive loss of consciousness, paralysis, convulsion, death
Chronic adverse effects of solvents
Neurotoxicity:
Sensory - e.g. visual, auditory
Cognitive - e.g. memory, confusion, disorientation
Affective - e.g. depression, apathy, nervousness
Motor - e.g. fatigue, tremor, in-coordination
Chlorinated solvents
Uses: paint removal, metal degreasing, cleaning
Acute: Irritant, liver, kidney, CNS depression, heart (arrythmias), lung (oedema)
Chronic: Fatigue, anorexia, liver, kidney; cancer (animals, non-genotoxic)
Aromatic solvents (benzene)
Uses: Rubber industry; paints, plastic & chemicals manufacture
Acute: CNS depression: nausea, ventricular arrhythmia, respiratory depression
Chronic: Headache, anorexia, weariness
Glycol ethers
Uses: resins, printing inks, textile dyes, varnish removers,
Acute: Irritant, nausea, liver, kidney
Chronic: Reproductive toxicity (male animals); developmental toxicity
(animal teratogen)
Ketones
Uses: paint, fats Solvent
Acute: Irritant, respiratory depression
Chronic: Peripheral polyneuropathy
Aliphatic hydrocarbons
Uses: Solvent in glues, paints, Fuel
Acute: Nausea, pulmonary irritation, ventricular arrhythmia
Chronic: Weight loss, anaemia, proteinuria, haematuria, bone marrow hypoplasia
Alcohols
Uses: Beverages, Antifreeze
Acute: CNS depression; irritant; GI tract
Chronic: Liver, immune function;
Plastics
Their monomers (& their metabolites) can be:
* very reactive with cellular macromolecules
* very cytotoxic (skin/respiratory irritation & hepatotoxic)
* carcinogenic
- Acrylamide also causes peripheral neuropathy
Gases
simple asphyxiants (N 2, Ar, He)
- displace oxygen from air
chemical asphyxiants (CO, HCN)
- block oxygen transport or utilisation
irritants (NH 3, Cl 2, O 3, SO 2, NO 2)
Particulates
Lung damage from particulates:
* respiratory allergy (grain dusts)
* mesothelioma, asbestosis (asbestos)
* silicosis (silica dust)
* irritation and allergies (engine exhausts)
Workplace (bio)monitoring
- contaminant conc. in workplace samples (e.g. air)
- biomarkers of exposure in workers
- levels of chemical/metabolite in blood/urine
- biomarkers of effect in workers
- biological response to chemical exposure
- biomarkers of susceptibility in workers
e.g. polymorphisms in human genes for important
xenobiotic-metabolising enzymes
DNA-reactive (genotoxic) carcinogens
- Activation-independent organics
(alkylating agents, nitrogen mustards, epoxides) - Activation-dependent organics
(aliphatic halides; PAH; arylamines; nitrosamines;
mycotoxins – aflatoxin AFB1; drugs – cyclophosphamide*) - Activation-independent inorganics
(Metals - Be, Cd, Cr as chromate, Ni;
metalloids - As; minerals - silica, asbestos)
Non-genotoxic (epigenetic) carcinogens
- Promoters: inhibits cell communication & contact inhibition
(liver enzyme inducer hepatocarcinogens - OC pesticides,
barbiturates, PCBs, PBBs, PCDDs - TCDD, saccharin) - Endocrine modifiers: for hormone-dependent tumours
- Peroxisome proliferators: not in primates?
- Cytotoxics: constant repair of damage stimulates cell growth
- Immunosuppressives: the immune system is the last line
of defence against tumours (NK & CTLs)
