As suggested, the disadvantage of the classic approach to target organ toxicity is that, too often, the organ is considered in isolation from other organs or from the rest of the organism. It is convenient to teach toxicology in this way, but it means that it can be difficult to cross-link information so that interrelationships are evident. In considering the toxicity of a chemical, it is important to keep the general view in mind; equally in looking at the effects in one organ or tissue, it is important to remember the rest of the organism. Paracetamol is one of the classic hepatotoxins but it also affects the kidney. Phenytoin, used in the control of epilepsy, can result in convulsions in overdose (it has a low therapeutic index or safety margin), chronic use is associated with gingival hyperplasia; it is a teratogen and can cause hypersensitivity with extensive dermal reactions. Lead has effects
Introduction to Toxicology: The Necessity of Measurement 25
Table 3 Factors in Target Organ Toxicity
Factor Examples
Blood supply Liver, kidney, and lung have greater blood supplies than adipose or muscle tissue
Oxidative exposure Lung and paraquat toxicity
Cell turnover Gastrointestinal mucosa, bone marrow, and toxicity of cytotoxic chemotherapies
Repair and reversibility Hepatic change may be easily repaired while change in the CNS is not
Physiology Concentration effects in the distal renal tubule
Morphology Length and diameter of axons in the peripheral nervous system Processing ability or
metabolic activity
Liver and xenobiotic metabolism. Renal proximal tubule versus the Loop of Henle. Oxygen concentrations
Hormonal control Reproductive tract and endocrine organs. Induction of hepatic metabolism and increased clearance of thyroid hormones Accumulation Lung and paraquat; adipose tissue and TCDD; cadmium in
kidney; lead in bone. Environmental accumulation of pesticides such as DDT
Protection mechanisms High concentrations of antioxidant GSH in the liver. DNA repair differences or deficiencies
Source: Adapted from Ref. 3.
on learning ability, in the nervous system, in the blood, and in the kidney and is associated with reproductive changes and may be carcinogenic. The susceptibility of organs to the effects of chemicals is influenced by a number of factors, some of which are discussed below.
There is a number of factors that influence the extent to which the effects of a chemical are expressed in particular tissues and these are summarized in Table 3 and expanded in the following text.
Blood Supply
The blood is the main vehicle for distributing chemicals of all kinds around the body, and it is logical that the blood supply is important in defining the degree of exposure of individual tissues to the chemicals in the blood, endogenous as well as foreign. The liver receives all the blood supply from the gastrointestinal tract via the inferior vena cava, from where it goes to the heart and thence to the lungs.
Thus, chemicals absorbed in the gut go to the liver, the main site of xenobiotic metabolism, and are distributed with any persistent metabolites to the heart and then on to the lungs and kidneys, which receive 25% of the cardiac output via the aorta.
26 A Guide to Practical Toxicology 2ndEdition
Oxidative Exposure
Much toxicity is due to oxidative attack on macromolecules and this is affected by blood supply and, of course, in the lung where the locally high concentration of oxygen is partly responsible for the high toxicities seen with compounds like paraquat.
Cell Turnover
Tissues that have an intrinsically high turnover of cells are at risk from chemicals that inhibit cell division. These include the mucosa of the gastrointestinal tract, the skin, the bone marrow, and the testes. Inhibition of the division in the bone marrow can affect the whole organism through induction of anaemia and/or reductions in the numbers of circulating leukocytes, in turn leading to reduced immune-competence. Where there is a high level of apoptosis, for instance, in developing embryos, disturbances in cell turnover have the potential to result in malformations in the foetus. Where cell turnover is increased, for instance, through necrosis with replacement through increased cell division, there are inherent risks of DNA replication errors, which can lead in the long term to tumor formation.
Repair Ability and Reversibility
An important aspect of assessing the significance of toxic effect is whether it is reversible, either on removal of the stimulus or through repair of tissue damage.
The extent to which tissues can repair themselves differs markedly according to tissue type and to an extent, embryonic origin. Some tissues are able to repair themselves readily, especially the liver. In rats, given toxic doses of carbon tetra-chloride, early evidence of liver damage seen in the plasma a few days after administration is frequently not reflected in histopathological evidence of damage after 14 days. This considerable capacity for self-repair means that it is possi-ble to miss toxicologically significant hepatotoxicity in standard acute toxicity tests, which require single administration followed by 14 days observation before autopsy. This repair capability is seen in humans following overdose with parac-etamol (acetaminophen) where there is often severe liver toxicity; in survivors, biopsy of the liver three months after the overdose sometimes shows no evidence of persisting liver damage.
Equally, some tissues do not readily repair themselves, especially the ner-vous system. In these tissues, regeneration does not take place or is very slow.
Whereas, a necrotic hepatocyte can be quickly replaced, a necrotic neuron is lost completely and the function of that part of the nervous system reduced pro-portionately. In some organs, particularly the kidney, different parts have differ-ent capabilities for repair. Thus, damage to the glomerulus and the renal pelvis is not readily repaired but the proximal tubule epithelium shows considerable repair capability, provided the basement membrane (on which the cells lie) is not breached.
Introduction to Toxicology: The Necessity of Measurement 27
Physiology
Cells or tissues with specific characteristics are susceptible to toxicants, which disrupt or take advantage of those characteristics. Paraquat is an example of this, through its accumulation in the lung, via the uptake mechanism for the endogenous polyamines. In the kidney, the passage of the urine through the distal tubule can lead to toxicity, as the toxins increase in concentration as water is reabsorbed.
Morphology
The length and small diameter of axons in the peripheral nervous system contribute to the axonopathy induced byn-hexane due to cross-linking of the microfilaments and subsequent poor nutrition of the distal parts of the cell. This is an instance where physiology is also important, as the axon depends on transport of nutrients from the neuronal body and appears to be unable to acquire them from elsewhere.
With the passage of nutrients blocked, the axon dies distally from the blockage.
Gross morphology is also a factor to be considered, if only rarely. When fed, the stomach of a rodent may press on particular lobes of the liver, restricting circulation in that lobe; this has been known to affect the distribution of liver tumors among the lobes, seen in response to carcinogens fed in the diet.
Processing Ability
Tissues that have high processing or metabolic activity are also frequent targets of toxicity. The liver has high activities of enzymes responsible for chemical metabolism and, therefore, if toxic metabolites are produced, they are likely to be produced in higher concentrations than in other tissues, increasing the risk of local effect. The difference between the liver and the lung in terms of enzymic activity is one of the determining factors in the toxicity of 4-ipomeanol. The proximal tubule of the kidney is another site of high metabolic activity and is a frequent target. High metabolic activity may also mean greater potential for oxidative attack through oxygen radicals, which can be produced as a result of normal metabolic processes.
The kidney is also at risk through its normal physiological function of producing concentrated urine; this can increase the exposure of cells in the nephron to a point at which toxicity is elicited.
Hormonal Control
Tissues that are subject to hormonal control will be affected when the concentra-tions of the relevant hormones are increased or decreased. When hepatic enzymes are induced in rats, there is often an increase in follicular hypertrophy or hyperpla-sia in the thyroid due to increased removal of thryoid hormones from the plasma as a result of the increased hepatic metabolism. The plasma levels of thyroid stim-ulating hormone are controlled by circstim-ulating thyroid hormone concentrations by negative feedback; where this feedback is reduced, the pituitary is stimulated to produce more thyroid stimulating hormone, which acts on the thyroid. The
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endocrine system is extremely complex and effects in one part can have a number of knock-on changes in other tissues.
Accumulation
Tissues that are able to accumulate specific toxins are also frequent targets for toxicity. Paraquat features here again in lung toxicity. Cadmium is widespread in the environment and accumulates in shellfish and plants. In mammals, cadmium is complexed with a metal-binding protein, metallothionein, which accumulates in the kidney. When a critical level of cadmium content in the kidney is reached—
generally quoted as being approximately 200g/g of kidney tissue in humans—
nephrotoxicity becomes evident and renal failure follows. Constant low intake at slightly raised levels can produce gradual accumulation over many years, which ultimately results in renal failure.
Accumulation in bone is a feature of toxicity of lead and strontium, which is a cause for concern if the strontium is the radioactive isotope. Bisphosphonates, used in the treatment of osteoporosis, also bind tightly to bone and this is a source of some of their toxicity. Environmental accumulation is also a factor to consider because it can have dire consequences, as illustrated by concentrations of fat-soluble compounds such as DDT, which increase in concentration up the food chain, as in bird of prey populations. DDT, and similar compounds such as TCDD, tend to accumulate in lipid tissue from which they are released very slowly. This is particularly a problem in species at the top of the food chain and has recently been acknowledged to be a factor in marine mammal toxicology.
At one time Americans were, by their own regulatory standards, inedible due to the amounts of DDT they had accumulated in their adipose tissue. For such compounds, toxicity can be expressed if there is a sudden loss of weight, reducing adipose tissue and releasing large amounts of toxin into the plasma where it can pass to the target organs, as in migration or pregnancy in malnourished people. In the development of brown-field sites, care must be taken that the residues of any industrial waste are considered in licensing use of the land, especially for growing food crops. This was a major source of toxicity at Love Canal in New York State, where a housing estate was built on a toxic waste dump.
Protection Mechanisms
Some tissues, particularly the liver, have high concentrations of endogenous com-pounds that have protective functions, normally against active oxygen species.
GSH, which may be present in the liver at a concentration of up to 5 mM, is a good example of this. Enzymes such as superoxide dismutase, which catalyzes the conversion of superoxide to hydrogen peroxide, are also important in protection of the cell. There are also differences between tissues in the activity of DNA-repair mechanisms. For example, the brain is less able than the liver to excise the DNA base guanine methylated at the O6position, making it more susceptible to tumor formation following administration of dimethylnitrosamine. Defective
Introduction to Toxicology: The Necessity of Measurement 29
DNA repair is also seen in patients with xeroderma pigmentosum, which gives a high incidence of skin cancer in response to exposure to UV light.
The problem in drawing such distinctions is the same as with describing toxicity in terms of target organs. A single chemical may be associated with effects in several organs and have a different mechanism of toxicity in each due to the differences in tissue susceptibility. This breadth of possible effects makes testing for toxicity extremely complex, until a mechanism is suspected. The enormous range of potencies of the chemicals to which we are exposed is an additional complication.