Lipophiles toxic mixtures

The toxic effects of lipophilic hydrophilic mixtures are not necessarily predictive of the ultimate toxic mechanism. Such mixtures induce the toxic effects by absorbing and transporting greater quantities of toxic chemicals to their ultimate sites of action. I2,3 ... 

The full health effect impact of the 287 toxicants found on the 10 babies tested is impossible to ascertain. The chemicals found include many lipophiles and hydro-philes and the combinations possible are almost endless. Further complicating the health picture is the continued exposure of these babies to the same and other xeno-biotics as they develop. Such exposure gives rise to still more 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. 

The chemicals listed in Tables 7.1 and 7.2 contain numerous hydro-philes and lipophiles. The number of mixtures possible is impossible to calculate. When people are stricken following exposure to polluted air, health effects are often attributed to an inordinately high concentration of a particular toxicant. An example of such a situation is what occurred in Bhopal, India, in 1984 when a huge quantity of methyl isocyanate was released from a chemical plant. Such single chemical effects, however, are the exception, rather than the rule. Most polluted air contains complex mixtures of chemicals that often produce effects that cannot be attributed to the known toxicology of the individual species. 

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... 

Formaldehyde is a major contributor to many cases of sick building syndrome. It is a very toxic chemical that is corrosive to the skin, eyes, and the respiratory system. Acute or chronic exposure can result in difficulty breathing and even brief exposures can induce asthmatic reactions in sensitized individuals. 13 Exposures to mixtures of formaldehyde and lipophilic chemicals can result in unanticipated toxic effects. 14 Formaldehyde is an animal carcinogen, a suspected human nasal cancer carcinogen 29 and suspected human leukemogen. 3°1... 

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. 

Fly ash from municipal waste and industrial waste incinerators contains polychlorinated dibenzo-p-dioxins (PCDDs), including tetrachlorodibenzo-/j-dioxin (TCDD) and polychlorinated dibenzofurans (PCDFs), which are lipophiles, and heavy metals, including chromium, copper, manganese, vanadium, and lead, which are hydrophilesJ29-31 These chemicals have multiple toxicities and are known to impact the human liver, immune system, respiratory system, thyroid, male reproductive function, and CNS J32 34l Several are human carcinogensJ32 35 Enhanced toxic effects are observed in the mixtures of some of theseJ21,22 36 The mixtures of toxicants present in fly ash are complex and the mechanisms for their action on the human body are largely unknown. It is known that occupational exposure to fly... 

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. 

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. 

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