Toxic actions

The acute and/or chronic nature of the toxicity of a chemical should be part of any decision-making process about its use or subsequent release. The focus cannot be solely on reduction of acute hazards, which tends to be easily achievable. The majority of cases in which chemicals have been released into the environment, only to cause serious ecological impacts over large spatial scales, were usually identified after many years, and at chronic low-dose exposures, with low acute toxicity to nontarget organisms. The classic examples of DDT and other chlorinated pesticides such as dieldrin and toxaphene, along with PCBs, exemplify the flaws in an approach that focuses on acute hazards, with more recent examples being the perfluorinated 

Now that we have discussed the types of exposures by which we may contact chemicals, this section introduces the concept of different types of toxic actions by chemicals. In general, there are two distinctly different categories of toxic action chemicals that cause cancer and those that do not. Within each category, there are many specific types of toxic action. These types of actions will be discussed in chapter 4. 

Although there are many types of cancers and some types do not conform with the typical development of cancer, in general cancer is the result of a series of events that results in uncontrolled cell growth. This process consists of four basic steps  

These mutations are within the cell, and usually impact how cell processes work. Mutations that cause changes to our appearance (e.g., cleft palate) are different than those that lead to cancer. Mutations at the cellular level occur constantly in our bodies. The vast majority of these mutations result in the death of the cell or they are repaired through our metabolic processes, ft is only when the mutation allows the cell to survive, escapes repair processes, and successfully replicates during cell division that initiation is considered to have occurred. This step is irreversible. This does not mean the cancer will then develop it means that if other events occur that allow these replicated, mutated cells to further multiply, cancer may develop. 

Promotion is the process whereby the mutant cells formed during initiation are transformed into cancerous cells. This can occur by stimulation of cell division or other processes. This stimulation can be caused by chemicals, or by specific genes within our cells that mistake the mutated cell for a normal cell. Cell processes can reverse this promotion up to a certain point. The end process of promotion is the presence of numerous cancerous cells that are stimulated to divide and grow. 

Non-cancer toxicity inciudes effects that injure specific or multiple organs or systems (e.g., alcohol and the liver, lead and the nervous system). The mechanisms are almost as numerous as the number of chemicals. Specific effects and examples of chemicals that cause them are discussed in chapter 4. The mciin point to mcike here is that, for non-cancer effects, a threshold level is assumed. Below this threshold level, no toxic effects are expected because there is not enough chemical present to overcome the defense mechanisms of the cell, organ, or system. Above this threshold level, toxic effects may occur because the defense mechanisms are overwhelmed. 

---

On the other hand, compounds corresponding to rather general, unspecific inodes of toxic action are distributed over a broad area in the respective layer, as shown for polar non-specific toxicants in Figure 10.1-14. 

Successful predictive models in toxicology exist - however, they are of a rather local nature. Effects considered in toxicology can be caused by different mechanisms. Efforts to get away from a class perspective to one that is more consistent regarding modes of toxic action are still a subject of ongoing research. 

Health and Safety Factors. Carbonyl sulfide is dangerously poisonous, more so because it is practically odorless when pure. It is lethal to rats at 2900 ppm. Studies show an LD q (rat, ip) of 22.5 mg/kg. The mechanism of toxic action appears to iavolve breakdowa to hydrogea sulfide (36). It acts principally on the central nervous system with death resulting mainly from respiratory paralysis. Little is known regarding the health effects of subacute or chronic exposure to carbonyl sulfide a 400-p.g/m max level has been suggested until more data are available (37). Carbon oxysulfide has a reported inhalation toxicity in mice LD q (mouse) = 2900 ppm (37). 

Thuringiensin (184), produced by B. thuringiensis (1,4) is a P-exotoxia that exerts its toxic action on insects and mammals through the inhibition of RNA polymerases. 

Acrylonitrile (Vinyl cyanide) CH,CHCN Closely resembles HCN in toxic action Poisonous by inhalation, ingestion or skin absorption Emits cyanides when heated or contacted by acids or acid fumes Symptoms flushed face, irritation of eyes and nose, nausea etc. Colourless flammable liquid with mild, faintly pungent odour Elash point 0°C. Dilute water solutions also have low flash points... 

The toxic action of bromine is similar to that of chlorine and can cause physiological damage to humans through inhalation and oral routes. It is an irritant to the mucous membranes of the eyes and upper respiratory tract. Severe exposures may result in pulmonary edema. Chronic exposure is similar to therapeutic ingestion of excessive bromides. 

The site of accumulation may define tlie point of toxic action. Inorganic mercury accumulation in the kidneys causes sever functional impairment Kidney damage has been shown to occur when the accumulated total of cadmium in the kidney cortex reaches 100-200 ppm... 

In the turnip, the concentration was 63 p.p.m. Toxic action against various insects was established. Two cabbage varieties, cauliflower, brussels sprouts, broccoli, kale, mustard, and kohlrabi also contain 2-phenylethyl isothiocyanate as evidenced by gas liquid chromatography and bioassay. Only root tissues had insecticidal activity. 

The biochemistry or mode of action of pyrethrum is not as well known as its chemistry. There are several theories of the toxic action of pyrethrum. Lauger et al. (26) consider that a highly effective contact insecticide must possess a toxic component (toxaphore) and must have groups attached which absolutely insure pronounced lipid solubility. They consider in the case of pyrethrins that in the cyclopro-... 

Cardiac glycosides have a small ratio of toxic to therapeutic concentration. Possible adverse effects are nausea, vomiting, abdominal pain, diarrhoea, fatigue, headache, drowsiness, colour vision disturbances, sinus bradycardia, premature ventricular complexes, AV-block, bigeminy, atrial tachycardia with AV-Block, ventricular fibrillation. There are several mechanisms relevant for their toxic action (Table 2). 

The negative effects of TBT have been observed in the bivalve larval development of Crassostrea gigas, Mylilus edulisf Venus gallina, Spams aurata, in Nassarius reticulate and in the hermaphroditic snails Phisa fontinalis and Adelomelon brasiliana Since TBT exerts a variety of toxic actions on some mollusks and fishes , an adverse effect of TBT on human health is a real threat. ... 

The monoorganotins do not appear to have any important toxic action in mammals 469,470,471), but they show the familiar pattern of decreasing toxicity with increasing alkyl chain-length, with the maximum again falling at the monoethyltin derivative (see Table V). 

Fuchs VS, Golbs S, Kuhnert M, et al. 1976. [Studies into the prenatal toxic action of parathion methyl on Wistar rats and comparison with prenatal toxicity cyclophosphamide and trypan blue]. Arch Exp Vet Med 30 343-350. (German)... 

Truhaut R, Gak JC, Graillot C. 1974. [Organochlorine insecticides Research work on their toxic action, its modalities and mechanisms. Part 1 Comparative study of the acute toxicity on the hamster and the rat.] Eur J Toxicol Environ Hyg 7 159-166. (French)... 

Flubendiamide is an example of a new chemical class of insecticides that have been termed phthalic acid diamides (Nauen 2006, Copping and Duke 2007). They are related to the alkaloid ryanodine, which is extracted from Ryania species. Ryanodine affects muscles by binding to calcium channels of the sarcoplasmic reticulum. Ca + ions act as intracellular messengers, and their flux is modulated by calcium channels of this type. The toxic action of ryanodine and synthetic insecticides related to it is due to the disturbance of calcium flux. 

A xenobiotic is said to be stored when it is not available to sites of metabolism or action and is not available for excretion. In other words, it is held in an inert position from a toxicological point of view, where it is not able to express toxic action or to be acted upon by enzymes. A xenobiotic is stored when it is located in a fat depot (adipose tissue), bound to an inert protein or other cellular macromolecule, or simply held in a membrane that does not have any toxicological function (i.e., it does not contain or represent a site of toxic action, neither does it contain enzymes that can degrade the xenobiotic). 

Tables 2.6 and 2.7 give examples of the modes of action of pollutants in animals and in plants/fungi, respectively. It is noteworthy that many of the chemicals represented are pesticides. Pesticides are designed to be toxic to target species. On the other hand, manufacturers seek to minimize toxicity to humans, beneficial organisms and, more generally, nontarget species. Selective toxicity is an important issue. Regardful of the potential risks associated with the release of bioactive compounds into the environment, regulatory authorities usually require evidence of the mode of toxic action before pesticides can be marketed. Other industrial chemicals are not subject to such strict regulatory requirements, and their mode of action is frequently unknown.

Pollutants Type of Toxic Action Site of Action... 

The mechanism of toxic action of some important organic pollutants is described and related, where possible, to ecotoxicological effects. 

Some biomarker responses provide evidence only of exposure and do not give any reliable measure of toxic effect. Other biomarkers, however, provide a measure of toxic effects, and these will be referred to as mechanistic biomarkers. Ideally, biomarker assays of this latter type monitor the primary interaction between a chemical and its site of action. However, other biomarkers operating down stream from the original toxic lesion also provide a measure of toxic action (see Figure 14.3 in Chapter 14), as, for instance, in the case of changes in the transmission of action potential... 

The acute toxicity of PCB mixtures to vertebrates tends to be low, typically, 1-10 g/ kg to rats. The concern is about sublethal and chronic toxicity. Different PCB congeners show different modes of toxic action, so it is not surprising that their mixtures can produce a disconcerting range of toxic effects (Robertson and Hansen 2001). 

---