Some six or so physiological systems, essential to normal mammalian life, are involved in poisoning; an
intoxication that causes severe injury to any one of them could be life threatening. Reversible chemical
reactions showing Scatchard-type binding are exemplified by CO, CN− and cyclodiene neurotoxin
insecticide intoxications, and by antigen–antibody complex formation. Haemoglobin (Hb) molecular
biology accounts for the allosteric co-operativity and other characteristics of CO poisoning, CN− acts as a
powerful cytochrome oxidase inhibitor, and antigen binding in a deep antibody cleft between two domains
equipped with epitopes for antigen-binding groups explains hapten-specific immune reactions. Covalent
chemical reactions with second-order (SN2) kinetics characterize Hg and Cd poisonings, the reactions of
organophosphates and phosphonates with acetylcholinesterase and neurotoxic esterase and the reaction
sequence whereby Paraquat accepts electrons and generates superoxide under aerobic conditions. Indirect
carcinogens require cytochrome P450 activation to form DNA adducts in target-organ DNA and cause
cancer, but a battery of detoxifying enzymes clustered with the P450 system must be overcome. Thus, S-metabolism competes ineffectively with target DNA for reactive vinyl chloride (VC) metabolites, epoxide
hydrolase is important to the metabolism and carcinogenicity of aflatoxins and polycyclic aromatic
hydrocarbons (benzo[a]pyrene, etc.), and the non-toxic 2-naphthylhydroxylamine N-glucuronide acts as a
transport form in 2-naphthylamine bladder cancer. VC liver-cancer pathogenesis is explicable in terms of
the presence of the glutathione S-transferase detoxifying system in hepatocytes and its absence from the
fibroblastic elements, and of the VC concentrations reaching the liver by different administrative routes. In
VC carcinogenicity, chemical reactions give imidazo-cyclization products with nucleoside residues of target
DNA, and in benzene leukaemia, Z,Z-muconaldehyde forms cyclic products containing a pyrrole residue
linked to purine. Increased HbCO concentrations reduce the O2-carrying capacity of the blood, and the
changed shape of the O2-Hb dissociation curve parallels disturbance in O2 unloading. CN− acts on electron
transport and paralyses respiration. In telodrin poisoning, preconvulsive glutamine formation abstracts
tricarboxylic acid intermediates incommensurately with normal cerebral respiration. Antigen–antibody
complexing depletes the antibody titre, available against infection. At high doses of Cd, Cd-thionein filtered
through the kidneys is reabsorbed and tubular lesions produced. Some organophosphate insecticides
promote irreversible acetylcholinesterase phosphorylation and blockade nerve function, and others react
with neurotoxic esterase to cause delayed neuropathy. The evidence for Paraquat pulmonary poisoning
suggests a radical mechanism involving three interrelated cyclic reaction stages. The action of N- and O6 (O
substituent in 6-position of the purine) demethylases explains deletion mechanisms for DNA-alkyl adducts.
DNA-directed synthesis in the presence of ultimate carcinogens provides for an estimation of
misincorporations, which implicate the same transversions as those found by direct mutagenicity testing.
Chemical carcinogens recognize tissue-sensitive cells and modify their heritable genetic complement.
Oncoproteins encoded by activated oncogenes signal the transformation of normal cells into cancer cells. The
importance of the H-ras oncogene and p53 tumour-suppressor gene is stressed. Antidotal action is analysed;
for example, parenteral glutamine administration to telodrin-intoxicated rats restores the depleted cerebral
glutamate level and prevents seizures. Glutamate acts as anticonvulsant in petit mal epilepsy. In general,
therefore, the reaction of the toxicant-related substance with the relevant target-tissue macromolecule
accounts for the biochemical/biological events at a cellular level and also the symptoms in the living
mammal. This mechanism is analogous to mechanisms for diseases such as arthritis and Parkinsonism.