Prophylactic toxicology and its role in occupational hygiene

PhD dosent Maximenko L.V.

Determination of prophylactic (industrial) toxicology

• Toxicology is an area of a science studying regularity and laws of interaction of toxic substance and human organism.

• Toxicodynamics studies the effect of toxic substances on an organism, toxicokinetics - an organism on toxic substances , toxicometrics - defines the sizes of zones of toxic action of toxic substances.

• Toxicometrics is the scientific basis of hygienic regulation of toxic substances with which workers contact at the production or application.

A toxic substance

• A toxic substance is a substance which at contact to an organism (at violation of safety rules) can cause poisoning, diseases or deviations in a state of health at contact period and in the remote terms of the life of the present and next generations and found out by modern methods.

Ways of penetration of harmful substances to an organism of the working person.

• Inhalation is the mainest way of penetration of chemical substances in to a working person organisme in ordinary conditions.

• Other pathways may take place either at the accidental release of substances or violation of safety rules.

1. Penetration through a skin and mucous membrane is typical for unelectrolits, partially soluble in water (4,5 group by Lazarev`s coefficient) since penetration through bilipidic layer of cellular membranes and solubility in blood is necessary; contact duration and area, temperature.

2. Penetration through a stomach is defined by the character and the degree of stomach fullness, structure of the intestine`s microflora & its secretory function. Toxins come from the stomach into the liver where there its metabolism and detoxication take place (but not always).

• Deposition of unelectrolits depends on blood supply of the body & sorbic capacity of tissues, physical and chemical properties of substance with a various degree of accumulation.

Phases of biotransformation of industrial toxins.

• 1 phase - oxidation-reduction reactions, hydrogenation, dehalogenation….

• 2 phase - synthesis of conjugates (intermediates) of a toxic substance with an endogenic compound:– with a glucuronic acid are formed glucuronides (with participation of -

OH, -COO, -NH2 and –SH groups), – with a sulfuric acid (it is characteristic for a detoxication of phenols), – with an acetic acid, – with amino acids:

• glycine - toxins with –COO-group - formation of hippuric=urobenzoic acid,

• cysteine – the aromatic hydrocarbons - formation of mercapturic acid,

• glutation - reactions of methylation and of acetylation are characteristic for heterocyclic compounds (pyridine, quinoline),

• Second stage of biotransformation is realized by enzymes, for example, glucuronidase at reaction with the glucuronic acid.

Cumulation of chemicals in an organisme• 1) Material cumulation: The material accumulation is tipical for

heavy metals. • Some heavy metals form stable complexes. Their stability

determines duration of the circulation in an organism, deposition in soft and parenchymatous bodies with an intensive blood supply (liver, kidneys, endocrine glands): – mercury and cadmium cumulate in parenchymatous tissue in the

form of a steady complex in fibers, – chrome collects in erythrocytes membranes,– lead, berillium and uranium cumulate in the form of phosphates

in bones.

• 2) Functional cumulation = accumulation of damaging effect (eg, death of hepatocytes in alcoholism). The functional cumulation is typical for polycyclic hydrocarbons (1,2,5,6-dibenzanthracene, 3,4-benzpirene), ДДТ - mainly in fat and give rise carcinogenic effect.

Allocation of toxic substances• The substances circulating in blood mainly are allocated

through kidneys.• The substances deposited in a liver (mercury, lead,

manganese) get into an intestine with bile and are allocated with faeces.

• The substances with a low water solubility (benzene, toluene, chloroform, xylol) evaporate through lungs or with mother`s milk.

• Organic solvents are removed through lungs in an unchanged form.

• The chlorinated insecticides besides cumulate in a fatty tissue. They can be defined in a subcutaneous fat from a wall of a stomach.

• Alcohol and brominatad hydrocarbons can be found out in a saliva, benzene - in a bone brain, thiophose - in a secret of sweating glands.

• Mercury and CS4 are allocated with a secret of glands.

Toxicological classification of harmful substances

The general toxic influence Toxic substances Nervously-paralytic effect (spasms and paralyses: bronchospasm, asthma…)

Skin-resorptive effect (local inflammatory and necrotic changes in a combination to the general toxic resorptivic effect)

General toxic effect (hypoxic spasms, a coma, brain hypostasis, paralysis)

Suffocating effect (toxic hypostasis of lungs)

Tear gas and irritating effect (irritation of external mucous membranes)

Effect on mentality (infringement of mental activity, consciousness)

Phosphorus organic insecticides (trichlorfon, nicotine, chemical war gases, etc.)

Dichloroethane, hexachloran, acetic essence, arsenic and its compounds, mercury (corrosive sublimate)

Hydrocyanic acid and its derivatives, carbonic oxide, alcohol and its substitutes, fighting poison gases

Nitrogen oxide, chemical war gases

A pair of strong acids and alkalis, chloropicrin, fighting poison gases

Chemical war gases, atropine

Neurotoxic substances

• Those substances to which thresholds of sensitivity of nervous system are essentially below, than thresholds of sensitivity of other organs and systems, and infringements of motor and touch functions of nervous system and memory, thinking, emotions, behavior lay in a basis of their intoxication, are conditionally carried to neurotoxic substances even if mechanisms of their toxic action aren't known.

Selective toxicity 1. Cardiac with primary cardiotoxic action: many medical

products, vegetative toxic substances, metal salts (salts of barium, potassium, cobalt, cadmium);

2. Nervous, causing mainly infringement of mental activity: carbonic oxide, organophosphorous compounds, alcohol and its substitutes, drugs, somnolent medical products, etc.;

3. Hepatic: first of all chlorinated hydrocarbons, phenols and aldehydes;

4. Nephritic: compounds of heavy metals, ethylene-glycol, oxalic acid;

5. Blood: aniline and its derivatives, nitrites, arsenous acid; 6. Pulmonary: oxides of nitrogen, ozone, phosgene, etc.

Possible effects of the combined influence of chemical substances on an organism

• Additivity is the summation of the effects at combined action (at absence of information about the combined effect of some chemicals it is made their additive effect) – mixture of hydrocarbons.

• Potentiation (synergism) is the enhancement of the toxic effect of a chemical substance by another.

• Antagonism is the effect of the combined influence less than the expected at additive effect (some toxic substances are antidotes for others: ethanol is an antidote for nitrobenzene and trinitrotoluene (trotyl).

• The combined effect is a fundamentally new effect, which is not observed for the separate toxic effects.

The most important characteristics of matter affecting its toxicokinetic parameters

• Distribution coefficient in oil / water determines the ability to accumulate in the appropriate medium: fat-soluble - lipid, water-soluble - in the water.

• Molecular size affects the ability to diffuse into the environment and to penetrate through the pores of biological membranes and barriers.

• Dissociation constant determines the relative proportion of molecules of the toxicant, dissociated in internal environment, ie, ratio of molecules in the ionized and unionized form. Dissociated molecules (ions) poorly penetrate through ion channels and do not penetrate the lipid barrier.

• Chemical properties determine the affinity of a toxicant to chemical and biochemical components of cells, tissues and organs.

Factors of occupational conditions acting on toxicity

1. Microclimate in working area (temperature and air humidity)

2. Effectiveness of exhaustion ventilation3. Physical heaviness of the labor process (frequency and

depth of breathing, the volume of air inhaled per unit time, heart rate, sweating

4. Body weight of worker 5. Age and state of health of worker6. Content of worker`s stomach (food, its quantity and

quality)7. Alcohol in blood8. Smoking9. Drugs 10. Medicine

N.V.Lazarev's (Overton-Maier) factor

• Narcotic (toxic) activity of organic substances is directly proportional to the Factor of substance distribution in oil/ water (coefficient of Lazarev).

• The rule of Overton-Maier: "Narcosis develops, when any chemically inert substance collects in lipidic cellular membrane in certain molar concentration".

• “The time allowed to gather evidence to support tht rule ” (Leading toxicologist of Russia S.A.Kutsenko, 2002).

Molecular structure of chemical substance and toxicity

• Richardson's Rule:• The force of narcotic action increases with increasing in number of carbon

atoms in homological series of alyphatic hydrocarbons (unelectrolits, narcotic substances).

• The increasing of narcotic effect goes only up to a certain member and then decreases. That is connected with the sharp decreasing of the solubility.

• Exceptions: the first member of a homologous series (methane and its derivatives) as a role shows a specific effect (a methanol - defeat of an visual nerve).

• Example 1. Narcotic effect amplifies in the series “propane - butane – pentane”, then decreases down to absence of the effect owing to more intensive decreasing in solubility of the subsequent substances in comparison with increase in their toxicity.

• Example 2. Toxicity accrues in the series from methyl alcohol (СН3-ОН) to pentyl alcohol (С4Н9-СН2-ОН). If to accept force of narcotic action of ethyl alcohol for 1 unit, the other spirits are expressed as: methyl spirit (СН3ОН) - 0,8; ethyl alcohol (С2Н5-ОН) - 1; propyl alcohol (С2Н5СН2-ОН) - 2; butile alcohol(С3Н7СН2-ОН) - 3; pentyl alcohol (С4Н9СН2-ОН) - 4.

• Narcotic action of hydrocarbons is characterized by additivity of the effect. With strengthening narcotic action hemolytic action of the substances increases also.

The dependence of the toxicity of aliphatic alcohols from their oil/water-solubility

Parameters

CH3-OH

C2H5-OH

C3H7-OH

C4H9-OH

C5H11-OH

C6H13-OH

C8H17-OH

LD50

Mouse

mM/ kg

intravenously

177 53.7 18.2 5.09 2.09 1.01 0.53

Hemolysis of rabbit erythrocytes

7.43 4.11 0.80 0.44 0.18 0.06 0.02

Inhibition of catalase activity on 50%

3.6 3.47 2.36 1.95 1.33 - -

The rule of branched out chains

• The force of narcotic (toxic) effect is weakened at branching of carbon atoms chain.

• Example (alyphatic spirits). Propyl or butyl alcohol are stronger drugs than corresponding them iso-Propyl and iso-Butyl alcohols.

Influence of structural isomerism on toxicity • A Plenty of the chemical substances, differing by

high toxicity, exists in the form of isomers which toxicity is various.

• Example 1. Para-isomers derivatives of benzene are more toxic, than meta-and оrtо-isomers: toxicity of isomers decreases in the series

– para-> meta-> оrtо-.

• Example 2. Among huge number of isomers of dioxins only 17 possess carcinogenicity (2,3,7,8).

Toxicity of cyclic compounds is more expressed

• Cyclic compounds are more toxic than corresponding them aliphatic compounds equal by quantity of carbon atoms.

• Example. Cyclopropane is more toxic, than propane, cyclobutane - than butane, cyclopentane - than pentane.

Toxicity of aromatic compounds is more expressed

• Toxicity of aromatic compounds is more expressed, than toxicity of cyclic compounds corresponding them.

• Example. Benzene is more toxic, than a cyclohexane, toluene - than methylcyclohexane. Chloro-benzene is more toxic than the chloro-cyclohexane .

The rule of multiple links

• Biological activity (toxicity) increases with increase in frequency rate of unsaturated links between carbon atoms.– Example. Acetylene (СН ≡ СН) is more toxic, than

ethylene (СН2=СН2) and in a greater degree than ethane (СН3-СН3).

• Narcotic and irritating actions amplify at increase in number of multiple links in molecules.

Group -OH decreases toxicity

• Presence of hydroxyl group (-OH) in a molecule increases its solubility in water and decreases its toxicity as a rule.

• Alcohols are less toxic, than corresponding hydrocarbons.

• Soluble in water substances (even with small molecular weight 50 - 100) possess the limited ability to get, for example, through mucous membranes.

• Example. Ethane is more toxic, than ethanol, a propane - than propanol, butane - than butanol, etc.

Halogens in a molecule of an organic substance intensify its toxicity

• Presence of halogens in a molecule intensifies the toxicity, specific damage of parenchymatic organ and irritating action.

• Example 1. Narcotic (toxic) action increases in a sequence of methane (СН4) < chloromethane (СН3Cl) < dichloromethane (СН2Cl2) < trichloromethane (chloroform) (СНCl3). Exception is represented by four-chloride carbon (СCl4) which possesses smaller narcotic action, than chloroform.

• Example 2. Irritating action decreases with reduction of quantity of atoms of chlorine in a molecule in a number

dichlorobenzene > chlorobenzene > benzene.

• The substances containing terminal halogen are more toxic, than the substances containing halogen, attached to a ring or the aromatic center.

• Example 3. Toxicity of chlorethylbenzene is expressed more, than ethylchlorobenzene.

• Cl-CH2-CH2-C6H5 > CH3-CH2-C6H4-Cl

Nitrogen-bearing substances acts just another than analogue without N-containing substances

• Introduction in a molecule of benzene or toluene nitro groups -NO, -NO2 or amino -NH2 groups sharply changes character of action of the substances: – Narcotic action of benzene and toluene containing –

NO, -NO2, -NH2 is not shown, – It is shown а specific action on blood (formation of

methemoglobin), on the central nervous system, on parenchymatous organs (degenerate changes)

• Example. For alkylethers of nitric and nitrogenous acids where groups -NO2 and -NO are connected with oxygen, there is typically vasodilating and vasohypotonic action (ethyl nitrite, amyl nitrite, ethyl nitrate, nitroglycerine).

Expansion of a molecule increases the probability of interaction of toxic substances with a biosubstratum (receptor) due to Van der Waals forces. • Endogenic bioregulators (neurotransmitters, hormones)

cooperate with receptors basically due to weak Van der Waals forces.

• Then more a molecule volume of a toxic substance, then greater number of its atoms contacts to a receptor-target site at linkage. Flexibility of conformational structure of a toxic substance molecule promotes affine linkage. Those toxic substances, which molecular structure is similar to a structure of endogenic biologically active substances, enter interaction with receptors, simulating their effects and carrying out agonist function.

– Example. This mechanism underlies toxic action of many alkaloids (nicotine, anabasine, etc.), glycosids, synthetic toxic substances, etc.

• If a toxic substance has essentially greater volume, than natural agonist its strong fixing on a receptor is carried out due to Van der Waals forces. It leads to shielding of receptors from substances-agonists or to their block (antagonists). – Example. Atropine and curarin accordingly to М-and

Н- cholinergic receptors operate by this way.

• The significant number of toxic substances acts as antagonists of corresponding molecules-bioregulators.

Occupational aerozoles

• Occupational aerosols dissolved in water (consequently in blood, lymph, extracellular and intracellular liquids) are considered as chemicals.

• Occupational aerosols undissolved in water are considered as fibrogenic dust causing fibrogenesis in lungs (occupational pneumoconiosis)

Possible effects of aerosole

• Industrial aerosols can render on an:– fibrogen, – toxic, – allergic, – ionizing, – photo sensitizer– carcinogen

Features of a fibrogenic dust:

• bad solubility in water; • presence of an electric charge on dust particles; • a crystal structure; • the wrong (not spherical) form of particles; • average dispersiveness (0,1 up to 10 microns) , • the maintenance of a dioxide of silicon.

Classification of industrial dust

• 1. on nature (organic – plant, animal, synthetic; inorganic – mineral, metal; mixed)

• 2. on particle size:– fine disperse with size of particles less than 0,1

microns, – average disperse with size of particles from 0,1 up to

10 microns (it is most dangerous as easily and deeply gets into lungs, but is difficultly deduced with slime at cough),

– large disperse with size of particles more than 10 microns).

WHO carries a fine dust to very dangerous with stochastic effect.

The CART denies presence of a threshold of action of an aerosol with the size of

particles 10 microns and less.

The stochastic (unthreshold) effect is shown that already at very small concentration in air at a part of the

exhibited persons probably development of pulmonary

diseases

• 3. On way of formation: an aerosol of decomposition (at crushing, grinding, polishing, cotton fiber pulling in textile industry and other processing of firm materials) and an aerosol of condensation (at receipt of steams of fused metals or other firm substances in rather cold air).

Pneumoconiosyses (the term is entered by Gippokrat). • miners and working in quarries, especially

in the sandy quarries, work coal, rock crystal and another minerals,

• extraction of metal ores

• metallurgy

• ceramic industry

• manufacture of a silicate brick

Variants of pneumoconiosis• Silicosis is caused by a dust containing a dioxide of

silicon SiO2 • Silicatosis - silicate dust: asbestosis, kaolinosis, talcosis• Antracosis, coal worker pneumoconiosis - coal

(anthracite) dust • Berylliosis – metalloconiosis (berulium)• Metalloconiosis: siderosis (iron oxide), berilliosis from a

dust of a beryllium, aluminosis, stannosis (tin oxide), and baritosis (barium sulfate particles)

• Bissinosis - dust of a cotton, • Bagassosis - dust of a sugar cane.• “Farmer's lung” – plant vegetable dust

Pneumoconiosis may be classified as either fibrotic or nonfibrotic, according

to the presence or absence of fibrosis.

Fibrotic forms of pneumoconiosis

• Silicosis, coal worker pneumoconiosis, asbestosis, berylliosis, and talcosis

Nonfibrotic forms of pneumoconiosis

• Siderosis, stannosis, and baritosis

Basic syndrome of a pneumoconiosis

• a fibrosis (sclerosis) of a pulmonary tissue in the form of a nodular fibrosis (at a silicosis, a berilliosis) or diffuse growth of a connecting tissue (at many forms of a pneumoconiosys).

• It can be accompanied by tuberculosis (silicosis, kaolinosis), lung cancer (asbestosis).

Silicosis

• The reason is the dust with the high maintenance of a dioxide of silicon (more than 70 %).

• 1 stage - poured fibrosis of lungs (on the roentgenogram blackout at roots of lungs) and dry cough,

• 2 - presence of the concentrated fibrous formations revealed only by means of a roentgenography (the roentgenogram as « a snow storm »), strong cough with a sputum,

• 3 - global defeat of lungs with a massive fibrosis, the strongest cough with a sputum and blood (hemoptysis) (in 80 % the tuberculosis joins).

• Death rate is very high. The latent period - from 46 working days till 1 year.

Byssinosis - occupational lung disease caused by inhalation of dust from cotton, flax, hemp or sisal. The patient always feels a sense of tightness in the chest and stridor after the weekend, which takes place during the week. The cause of the disease has not been established.

Bagassosis (sugar cane waste) - allergic alveolitis caused by repeated inhalation of dust extraction product of sugar cane (bagasse) from the contained spores of fungi.

A 66 year old man had inhaled cotton fibre for 50 years at his workplace. He did not have any respiratory symptoms. Chest CT scans revealed diffuse centrilobular and peribronchovascular interstitial thickening. Lung biopsy specimens confirmed the presence of string-like foreign bodies as well as granulomas and fibrosis in the peribronchial region. Infrared spectrophotometry confirmed that the foreign bodies were composed of natural cellulose. This is the first study to show directly by examination of biopsy samples that cotton fibre inhalation can cause diffuse lung disease. The clinical features of the disease were entirely different from those of byssinosis [H Kobayashi, S Kanoh, K Motoyoshi, S Aida. Diffuse lung disease caused by cotton fibre inhalation but

distinct from byssinosis// Thorax 2004;59:1095-1097].

Preventive maintenance of occupational dust diseases

• 1. reduction of a dust content of air of a working zone:

• modernization of production technology,• introduction of technical automatic control;• hermetic sealing of the equipment containing

dustforming materials;• water flushing of dust• 2. mechanical local exhaust and common

exchanging ventilation with prevalence of an extract.

MPC• 3. establishment and sanitary observance of maximum

permissible concentration of aerosols in air of a working zone:

• >70 % of SiO2 in dust = 1 mg/m3, • from 10-69 % SiO2 = 2 mg/m3, • SiO2 <10 % = 4 mg/m3,

• Without SiO2 =10 mg/m3

• asbestos and glass dust = 2 mg/m3, • soot = 4 mg/m3, • anthracene dust = 5 mg/m3.• flour dust = 6 mg/m3 • untoxic sugar and coal dust = 10 mg/m3 • + many mixed dust on specific technology…

Individual defence

• - respirators of disposable use or with replaceable filters, antidust glasses and overalls from a dustrepulsive material (cotton impregnated by dustrepulsive chemical substances)

Sanitary-educational and medical work

• 1. Recommendations on personal hygiene:– regular rinsing of a mouth by water or a solution of

soda, – larynx inhalation by soda solution in a medical and

sanitary establishment at the industrial enterprise– regular cleaning of a teeth by alkaline teeth past.2. Preliminary and each 6 months periodic medical

surveys with an obligatory lungs roentgenography and check of functions of external breath