Compounds of Lead

The development of catalytic converters for combustion of unburned hydrocarbons prohibits a return to lead compounds and henceforth refiners are turning to oxygenated compounds that must be used as a gasoline component therefore, in amounts much greater than those of lead compounds. 

The protection of the environment implies the elimination of lead compounds, first of all because of their individual toxicities and second because these derivatives or their products of decomposition poison catalytic converter catalysts. 

Once a number of lead compounds have been found, computational and laboratory techniques are very successful in rehning the molecular structures to yield greater drug activity and fewer side elfects. This is done both in the laboratory and computationally by examining the molecular structures to determine which aspects are responsible for both the drug activity and the side effects. These are the QSAR techniques described in Chapter 30. Recently, 3D QSAR has become very popular for this type of application. These techniques have been very successful in the rehnement of lead compounds. 

Calculating the Maximum Quantity of Lead and Lead Compounds. To calculate the maximum amount of lead and lead compounds present at your facility at any one time, you must consider types of metallic load and M types of lead compounds present at your facility, Including stockpiled raw materials, lead and lead oxide present in process equipment, the metallic lead and lead peroxide contained in finished batteries stored on-site, and stockpiled lead scrap. Since the reporting form is being prepared for lead compounds, the maximum amount reported is the total of the inventories of these materials. The maximum amount of metallic lead (2,305,000 pounds), lead oxide (205,000 pounds), and lead peroxide (625,000 pounds) present at your facility is 3,135,000 pounds, which is between 1,000,000 and 9,999,999 pounds. You would therefore report range 06 on Part III, Section 4, of the reporting form. 

Some elements come in and out of fashion, so to speak. Sixty years ago, elemental silicon was a chemical curiosity. Today, ultrapure silicon has become the basis for the multibillion-dollar semiconductor industry. Lead, on the other hand, is an element moving in the other direction. A generation ago it was widely used to make paint pigments, plumbing connections, and gasoline additives. Today, because of the toxicity of lead compounds, all of these applications have been banned in the United States. 

Toxicology Many companies are known to use gene expression profiling to assess the potential toxicity of lead compounds. This approach may require a database of reference compounds with known pharmacological and toxicological properties. Lead compounds can be compared to the database to predict compound-related or mechanism-related toxicity [5]. 

Cruciani G, Pastor M and Guba W. VolSurf a new tool for the pharmacokinetic optimization of lead compounds. Eur J Pharm Sci 2000 11 Suppl 2 S29-39. 

The last step of the drug discovery process involves the testing of lead compounds to address issues such as efficacy, bioavailability, and safety. Testing may include in vitro assays but ultimately would require a suitable disease model and studies in animals. Many compounds may need to be designed and synthesized to identify the one compound with all the desired properties. Such a compound can be advanced to preclinical studies and eventually to the clinic. 

Figure 5.1 Compound evaluation flowchart for postscreening characterization of lead compounds.

Graphing and fitting of the inhibtor concentration-response data to obtain the IC50 is typically the primary mechanism for assessing the relative potency of lead compounds and lead compound analogues (see below). The IC50 can be determined by... 

If the inhibitor is found to bind rapidly (linear progress curves) and dissociate rapidly (rapid recovery of activity upon dilution) from its target enzyme, then one can proceed to analyze its inhibition modality and affinity by classical methods. The modes of reversible inhibition of enzymes were described in Chapter 3. In the next section of this chapter we will describe convenient methods for determining reversible inhibition modality of lead compounds and lead analogues during compound optimization (i.e., SAR) studies. 

Experimental Studies on the Ingestion of Lead Compounds. The Journal of... 

Oral LD50 values for lead or its inorganic or organic salts were not found in the available literature. LDl0 values for a number of lead compounds have been estimated (Sax 1984, see Table 2-3). An LDlo is defined as the lowest dose of a substance given over any given period of time in one or more divided portions reported to have caused death (Sax 1984). Furthermore, unlike LD50 values, these values are not derived statistically, and comparisons between compounds and species are difficult. 

Developmental Effects. Evidence from human studies on congenital anomalies as an end point (Emhart et al. 1985, 1986 McMichael et al. 1986 Needleman et al. 1984) indicate no association between prenatal exposure to low levels of lead and the occurrence of major congenital anomalies. This conclusion is further supported by developmental toxicity studies conducted in rats and mice these studies provide no evidence that lead compounds (acetate or nitrate) are teratogenic when exposure is by natural routes (i.e., inhalation, oral, dermal). Intravenous or intraperitoneal injection of lead compounds (acetate, chloride, or nitrate) into pregnant rats, mice, or hamsters, however, has produced malformations in several studies reviewed by EPA (1986a). 

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