Hydrophiles toxic mixtures

The second innovative peculiarity is the application of HRA-oriented in vitro investigation a human in vitro model has been used to obtain more information on the effect of leachate exposure and toxicity accounting of not only the toxicity of hydrophilic and lipophilic compounds but also the effects of whole leachate as a complex mixture. 

Common unspecific mode of action of all organic compounds has been taken up in quantitative structure-activity relationships (QSARs see Chapter 5) as the concept of baseline toxicity and in toxicokinetics as the body burden concept (see Chapter 2). Baseline toxicity refers to the idea that a minimum toxicity expectation may be formulated for any given organic compound based on considerations of a compound s partition properties between hydrophilic and lipophilic chemicals (e.g., between water and octanol). Commonly, this is expressed in terms of the octanol-water partition coefficient (K0,J of a chemical. The partition coefficient allows estimations of a local concentration or body burden for each individual chemical in the mixture. Assuming that this produces the same toxic effect (disturbances of cell membranes), it is then possible to anticipate joint narcotic action by adding together the respective local concentrations or body burdens for each individual mixture component. 

Traditional toxicology addresses the toxic effects of single chemicals and even some mixtures (additivity, potentiation, and synergism) well, but it is unable to account for some observed effects of chemical mixtures. These unexplained effects often ensue when exposures are to mixtures of lipophilic and hydrophilic chemicals. Octanokwater partition coefficients serve to predict the lipophilic or hydrophilic nature of chemical compounds. 

Witte et al. determined that subtoxic concentrations of membrane-damaging compounds enhanced the cytotoxicity of hydrophilic xenobiotics (foreign compounds) J11 The data reported show a linear relationship between the logarithm of the no observed effect concentration (NOEC) and K)w values the higher the K, the lower the log NOEC value and greater the toxicity of the mixture. The data in Table 3.3 show Kjw and NOEC in millimoles (mM) for 2,4-dichlorophenoxyaceetic acid (2,4-D). The sole deviant from the relationship, tributylamine, is explained by its extremely low membrane-damaging properties relative to its lipophilicity. 

At times, such as in drug administration, lipophiles are deliberately added to hydrophilic pharmaceuticals to facilitate absorption. Most often, however, the administering of combinations of lipophilic and hydrophilic chemicals is unintentional and leads to enhanced toxic effects on the body. Once taken up by the body, the distribution, metabolism, immune system response, endocrine system response, and effects on a wide variety of organs in the body are impacted by the mixtures and their metabolites. 

The examples of the effects just described are, unfortunately, few in number. This makes predicting the toxic effects of mixtures very difficult and underscores the importance of the empirical approach. As discussed in Chapter 2, it has been found empirically that human exposure to combinations of lipophiles and hydrophiles produces unanticipated effects. The underlying mechanism (s) for this phenomenon remain unknown. 

There are no known direct studies on the toxic effects of chemical exposures on the developing fetus. It is known, however, that children of tobacco smokers (tobacco smoke is a mixture of multiple lipophiles and hydrophiles) have unusually high incidences of ADHD, autism, and other developmental disorders. These and other mixture effects are examined more closely in subsequent chapters. This chapter has aimed to alert the reader to the fact that toxic exposure begins at conception and impacts the fetus throughout gestation and beyond. 

Water pollution causes the introduction of a very wide variety of toxic chemicals to those drinking, cooking, and bathing with impure water. There are numerous sources of pollutants that end up in potable water, and the mixtures produced by many of these pollutants result in unexpected toxic effects in people who consume such water. Mixtures of lipophilic and hydrophilic chemicals have been demonstrated to be causative for many of these unanticipated toxic effects. 

Contaminated sites such as industrial chemical dumps contain mixtures of numerous toxicants. These include multiple lipophiles and hydrophiles that can undergo chemical reactions, migrate, and be absorbed by plants and animalsJ30 Such sites are often acutely and chronically toxic, environmentally persistent, and lead to bioaccumulation of toxicants in food webs. An excellent example of such a site is the Love Canal in the state of New York. 

Most of the chemicals in Table 11.2 target the respiratory system and CNS. Exposures in arts and crafts use are almost always to mixtures of lipophilic and hydrophilic chemicals. When used in areas with poor air circulation (as is often the case in home use) the result can be unexpected acute toxicity. For example, it has been reported that exposure to formaldehyde and terpene hydrocarbons at very low levels unexpectedly produced dyspnea and other lower-lung symptoms in wood workers. The effects could not be attributed to either the formaldehyde or the terpenes alone at low levels of exposure In another example, it was reported that chronic exposure to a combination of very low concentrations of MEK, ethyl acetate, and aliphatic hydrocarbons in a leather adhesive formulation induced unanticipated CNS effects. Some products that are considered by most... 

Most household maintenance products contain mixtures of lipophiles and hydrophiles that can produce unanticipated toxic effects. Irritant-induced asthma is an example of such an effect. Solvent-based and waterborne paints contain solvents that are nonsensitizing irritants that are individually not known to induce asthma. Despite this, exposures to both types of paints have been shown to cause the asthma-like condition reactive airways dysfunction syndrome (RADS).I13 14 RADS is discussed in detail in Chapterl8. 

Chemical mixtures in cosmetics give rise to enhanced toxicity, low level toxicity, and unexpected target organ attack. Cosmetic products are composed of many lipophilic and hydrophilic chemicals. Numerous instances of strange injuries, including chemical burns and skin and respiratory sensitization from the use of cosmetic products, have been documented in which the injuries sustained could not be accounted for by a consideration of the individual chemicals involved J3°l... 

In almost all of the studies presented here (as well as in most others not reported here) the chemical mixtures that produced unanticipated toxic effects contained at least one lipophile (K > 2.00) and one hydrophile ( CW < 2.00). The octanol water partition coefficients (7T w) are given in parentheses for each of the chemicals identified to point out the lipophilic and hydrophilic species. 

On-the-job exposures offer insight into the toxic effects of chemical mixtures. Though many health effects can be attributed to exposures to single chemicals, others cannot be accounted for by single chemical exposures and are clearly related to exposures to mixtures. This is particularly the case when at least one component of the mixture is a lipophile and at least one other component of the mixture is a hydrophile. The studies referenced in this chapter point out the need to consider mixture exposures when people present with symptoms, rather than dismiss their complaints as being of psychological origin. 

Low levels of an applied herbicide-pesticide-solvent mix were drawn into the uptake air of a commercial building following the application of a pesticide mix to the lawn in front of that building. Several employees immediately reported CNS and respiratory symptoms, with one sustaining a permanent respiratory injury. The pesticide mix applied to the lawn was composed of 2,4-D (2.82), 2-(2-methyl-4-chlorophenoxy) propionic acid (MCPP 2.48), and dicamba (2.21). The mixture also contained solvent naphtha (a mixture of aliphatic solvents, Kqw = 3.5-5.0) with 14% naphthalene (2.48) and dinitroaniline (3.30). The concentrations of all pesticides and solvents were far below the TLVs both outside and inside the building. The toxic effects observed were ascribed to the mixture of lipophilic and hydrophilic pesticides. 441... 

All the low level pesticide effects discussed earlier, ensued following exposures to mixtures that contained lipophilic and hydrophilic components. This is consistent with the manner in which pesticides are formulated and applied, that is, as mixtures of products, each of which is composed of lipophilic and hydrophilic components. An exhaustive search of the literature did not produce a single example of low level pesticide activity at concentrations at which the pesticide mixtures exhibited toxicity. 

Cigarettes, cigars, pipe tobacco, and smokeless tobacco are made up of dried tobacco leaves and hundreds of other components added for flavor and other properties. More than 4000 individual toxic lipophilic and hydrophilic chemical compounds, of which greater than 60 are carcinogens, have been identified in tobacco and tobacco smoke. I35 36 Accordingly, all tobacco and tobacco smoke exposure is, of necessity, to mixtures of toxic chemicals. 

This section is devoted to chemical mixtures that are respiratory irritants. Irritants do not induce immunochemical responses, and irritation in non-sensitized individuals generally leads to slower, less serious respiratory responses and usually requires higher doses of toxicants to produce symptoms than in sensitized people. Irritant-induced inflammation responses (e.g., bronchial hyperactivity) can be severe and prolonged but, by definition, do not result in sensitization of those so exposed. Mixtures of lipo-philes and hydrophiles induce irritant respiratory system responses at concentration levels that are below those for the single chemicals. This phenomenon is well demonstrated by exposures in sick buildings. ... 

Particulates are another source of respiratory irritation when inhaled. In urban environments, diesel exhaust particles and fly ash residue from power plant oil combustion are the main contributors of respirable particulates of less than 10 pm diameter (PM 10). These contain mixtures of lipo-philes and hydrophiles including various metals, acid salts, aliphatic hydrocarbons, PAHs, quinones, nitroaromatic hydrocarbons, andaldehydes. 151 Diesel combustion particulates contain large surface areas that can adsorb large quantities of organic compounds and deliver these to respiratory tract tissue. Other inhaled particulates can adhere to lung surfaces and adsorb and bond other vapors that are inhaled, thereby increasing their toxicities. PM2.5 particulates (those with diameters of less than 2.5 pm) that reach the lower respiratory tract as far as the alveoli are more toxic than PM 10 particulates of the same composition. 16 ... 

Not all mixtures that are toxic to the respiratory system are mixtures of lipophiles and hydrophiles. In some instances, irritant chemicals react to produce more toxic species. Chloramine-induced pneumonitis from the mixing of household ammonia and bleach is an example of this phenomenon. 100 101 Household ammonia cleaner is usually a 5-10% aqueous solution of ammonia. Household bleach is generally a 5.25% solution of sodium hypochlorite. At these concentrations, these chemicals alone act as respiratory irritants. When mixed together, however, they react to form monochloroamine, dichloroamine, and trichloroamine as shown in Fig. 17.1. Chloramines are far more toxic than either hypochlorite or ammonia and are capable of producing inflammation and edema of the respiratory system. Case 14 is an example of the toxicity of chloramines. 

These metals are all hydrophiles and though their allowable quantities are low, they may nevertheless form neurotoxic mixtures with lipophilic species from other dietary items and have toxic impact. No studies have yet been carried out on the allowable levels of these heavy metals in dietary mixtures containing colors, flavors, and preservatives. A search of the literature did not reveal other studies related to the Feingold diet that analyzed for or considered the effects of lead, arsenic, and mercury. 

As seen from the data, water disinfected with chlorine can have a complex mixture of lipophiles and hydrophiles. The lipophilic THMs can facilitate the absorption of the hydrophilic haloacetic acids, haloace-tonitriles and haloketones. An analogy between the reproductive toxicity and carcinogenicity of DBPs can be drawn. Though no single chlorinated byproduct studied appears to be carcinogenic, there is evidence from animal studies that DBP mixtures are carcinogenicJ4°l... 

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