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Narcosis (Aquatic Toxicology)

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Chlorobenzene
The Chlorobenzene Molecule is a type of polar narcotic
Chlorobenzene molecule is a type of molecule that can produce Narcosis II effects (polar)

Narcosis is a non-specific reversible mode of action, which is a state of decreased biological activity that results from exposure to a wide variety of chemicals [1][2][3][4]. All organic chemicals can cause some level of narcosis at high enough levels [5]. FATS (fish acute toxicity syndrome) are useful for distinguishing organismal response to organic chemicals from narcosis [1][3]. There are two known types of narcosis: Type I and Type II. Type I narcosis is known as “nonpolar” or “baseline” narcosis due to the non-polar organic chemicals that cause its effects [1][5][5]. Type I narcosis is used as a baseline for toxicology testing. Type I narcosis may cause biological depression, lethargy, and death at high enough exposure concentrations [1][2]. Hydrophobic bonding within enzymes within the central nervous system is believed to be the cause of inhibition by Type I narcotics [1][2][4][6][5][7]. Type II narcosis is known as Polar Narcosis due to the increased solubility of the chemicals in water [1]. The increased toxicity of polar narcotics is believed to be due to greater level of hydrogen bond acidity within these polar chemicals [1][2][6][5][3]. Type II narcosis is associated with an excited response within an organism [2][3]. Both Type I and Type II narcosis are commonly used in toxicity predictions through the use of QSAR (Quantitative structure-activity relationship) modeling [1][6][3].Type 1 Narcosis has been found to be be the less toxic of the two types of narcosis due to its less specific mechanism of action [1]. Furthermore, QSARs are used as a method to predict chemical activity through isomers as a way to attempt to determine the effects of unknown compounds [2]. QSAR’s for narcosis can be in Kow and Kmw, where Kmw demonstrates the membrane/water partitioning coefficient and is often seen as another measurement in narcosis for narcotics interact with the cell membranes [8]. The Kow of a chemical can additionally be used within QSARS to capture the hydrophobicity of the chemicals as it relates to its narcotic effects [2]. Furthermore, FATS can be used to aid in management of narcotic effects within organisms.



Causation of Narcosis

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Narcosis has been found to be a reversible, nonspecific mode of action that results in the decrease in biological activity within organisms [1][2][9][10][6]. It was first described by Meyer and Overton in the late 19th and early 20th centuries [2][5][9][7][3]. A wide range of organic chemicals have been found to cause narcosis within organisms [1][5][4][9]. Two types of narcosis have been defined: Type I (nonpolar/baseline/neutral) and Type II (polar) narcosis. Type I narcosis has been found to be the less toxic of the two types due to its less specific mechanism of action [1]. Type II narcosis is thought to be five to ten times more toxic than Type I narcosis [3].

Narcosis I

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An Adverse Outcome Pathway (AOP) general Narcosis. Adapted from Ankley et al., 2010, and Landis et al., 2017

Type I narcosis is characterized by lethargy, unconsciousness, and death due to decreased cardiovascular and respiratory function [1][2][9][11]. However, there is a notable lack of hyperventilation, erratic or convulsive behavior, or hemorrhaging with Type I narcosis [1]. Examples of Type I narcotic compounds include alcohols, ethers, ketones, and aldehydes [1][2][12][9][6][11]. Type I narcotics are thought to be additive in effect when present in mixtures in the environment [1][7]. In terms of acute versus chronic exposure, during chronic exposure, vertebrates have been found to be more sensitive than invertebrates to nonpolar organic chemicals [13]. Organic chemicals that are suspected of being Type I narcotics tend to exhibit toxicity within a narrow range of concentrations [5]. However, there is still a wide range of toxicity values, which makes creating an accurate dose response for Type I narcosis more difficult [5].

Narcosis II

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Type II narcotics are defined as such due to their increased solubility in water [1]. The increased toxicity of Type II narcosis is thought to be due to the greater dipolarity and/or the hydrogen bond acidity of these chemicals [1][2][13][12][9]. Specifically, Type II narcotics have been hypothesized to act as either the donor or acceptor molecule in forming hydrogen bonds [12]. It has also been hypothesized that the difference between Type I and Type II narcotics is due to the polar nature of the chemicals associated with Type II narcosis [12][3]. Chemicals classified as polar narcotics are distinguishable by their electrophilicity, hydrophobicity, and their reactivity [3]. Examples of Type II narcotics include esters, amines, nitroaromatics (nitro compound), aniline, phenols, and pyridines [2][4][9][10][3][11]. In general, Type II narcotics are thought to cause hyperactivity within organisms [11]. Specifically, within fish, Type II narcotics have been noted to create excitatory responses and induce clonic seizures initiated by a cough response [2][9]. Type II narcotics have been found to have higher PKa values[5].[2].[9].[10].[13].[6].[11].[5]. LC50, Kow, and pHa values have also been found to be important in distinguishing between Type I and Type II narcosis and describing Type II narcosis [2][13][12][4][9][10][3][14]. As the Kow increases beyond 2.7, there was a more moderated effect of hydrogen bond affinity within polar narcotics [2]. However, other descriptors are needed to fully understand the mechanism behind Type II narcosis [13]. Non-ionized forms of chemicals have been found to be more toxic than ionized forms of chemicals due to the non-ionized form being able to pass through the gills of fish faster than ionized forms [13]. Similarities between fish and mammals have been noted with narcosis, which has been hypothesized to be due to the nonspecific nature of narcosis [10].

Mode of Action

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Narcosis is thought to affect central nervous system membranes [13][9][11]. Type I narcosis is thought to interact through 3D partitioning in the membrane, while Type II narcosis is thought to interact through 2D partitioning [11]. Narcotic molecules might have multiple mechanisms of action and affect multiple sites within an organism, thus causing cell membranes to become inoperative[6] [11]. The hypotheized mode of action for narcotic chemicals is due to the swelling or disruption of lipids within cell membranes or by a relationship between receptors and protein pocket target sites [2][5]. For example, phenols, which are Type II narcotics are thought to affect energy production within cells by inhibiting electron transport or by causing an imbalance in the proton gradient present within membranes[6][11]. Neutral narcosis has been found to be very similar to anesthesia and that for both, hydrophobic binding to the target site(s) occurs [1][2][5][9][6][13]. Further evidence has suggested that the receptor site for narcosis is protein enhanced, lipid-rich site that is associated with transmembrane ion channels[5]. This is because that organic chemicals partition within organisms based on their affinity for the various compartments within an organism [2][5]. Thus, lipid content and receptor sites within organisms in unlikely to remain constant as these vary within and amongst species. Separate receptors have been noted for different mechanism of action, such as with the brain and spinal cord [5].

Critical body residues (CBRs) have also been hypothesized to affect the mode of action and subsequent toxicity of narcotic chemicals within aquatic organisms [5]. The critical body residue has been found to be a better description of toxicity within organisms than other metrics such as an LC50 due to CBRs being a measurement that is determined closer to the target site within an organism. Thus, CBRs are less dependent on routes of exposure, such as water, and varying exposure conditions and can be compared with internal exposure measurements and/or models [5]. However, narcosis has been found to not be completely correlated to CBRs as CBRs can differ by species and nonnarcotic modes of action can affect narcosis CBR variability [5]. To create a more accurate toxicity approach using CBRs, lipid content and character, biotransformation, toxicity time dependence, and receptor-mediated toxicity have been deemed important components of this analysis [5].

Introduction into the Environment

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Red dotted highlight indicates the separation of hydrophilic to hydrophobic regions at log kow of 1.5. The orange line demonstrates the predicted LC50, the green line represents bioconcentration for fish, the light blue line represents the body residue. Figure adapted from McCarty et al., 1992.

Contamination can come from many sources in the environment, especially those close to locations of human development. There are over 80,000 known chemicals on Earth, which includes narcotic chemicals that are created and produced in many consumer products [15][16]. Narcotics enter into the environment in multiple ways, such as through product usage and dispersion, direct dumping, contamination, road runoff, prescription drug contamination, sewage, and garbage treatment [16]. Based off of ecological risk assessments, it has been determined that within aquatic environments, approximately 60% of chemicals present can induce narcosis [1]. When chemicals get into a water body, the properties of the chemical can change from interaction with different water quality parameters such as hardness, dissolved oxygen, water flow, and differences in Kow [13][8].

Furthermore, narcotic chemicals have the ability to change their potency in the body residue of aquatic animals depending on the concentration of log Kow values of the chemical. If a narcotic chemical contaminates an aquatic location with a value of log Kow that surpasses that of 1.5, a trend is seen where the lethal concentration decreases as lipid accumulation of chemical increases [11][17][18]. At the value past log Kow 1.5, chemicals concentrate more in the lipids due to the increase of the bioconcentration factor and lipophilicity thus an increase in lethal body residue and a decrease of LC50 is exhibited for a particular narcotic[11][17][18]. At any value below that of log Kow 1.5, it is shown that chemicals act hydrophilic where the bioconcentration of the chemical is similar to that of water and chemicals do not tend to accumulate in the lipids [17][18].

In this way, environmental management of contaminated locations can be used in collaboration with other elements for baseline narcosis to aid in chemical identification and/or environmental assessment of a potential threat [4][8][11] [17]. Furthermore, an ecological risk assessment can be used to identify the potential severity of a pollutant in a particular contaminated location. An example would be to take water quality data from a particular contaminated location, establish baseline narcosis data to compare against, utilize previously established QSARs, and then conduct calculations to see if a chemical is hazardous to a particular environment [8] [11][17]. For chemical identification, water quality parameters for a contaminated locations can be plotted against that of baseline narcosis to see is a chemical exhibits an effect [3][8][12].

QSAR Testing and Baseline Narcosis

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Quantitative structure-activity relationship (QSARs) are models, which require creating a mathematical relationship that relates the structure of a chemical to subsequent biological activity [2][13][12][3].

A generic QSAR linear regression model. Adapted from Landis et al., 2017 and Roberts and Costello, 2003.

QSARs assume that toxicity is related to the concentration of a chemical at a site of action [2]. However, QSARs can only be used to relate between compounds with similar modes of action and separate QSARs must still be created given that each QSAR can only be used for a given structure [12][9][3]. For example, QSARs can be used to assess the level of toxicity associated with a chemical and can be used to distinguish between Type I and Type II narcosis [1][13][11]. QSARS are especially useful for describing estimates of toxicity for chemicals that are Type I narcotics [9]. Furthermore, QSARs are usually used to estimate the toxicity associated with narcotics and the lipophilicity of organic chemicals [13]. Although it has been found that these QSARs do not predict the full toxicity of either Type I or Type II narcosis as actual toxicity has been found to be higher than these predictions [1][9]. However, QSARs can still be created for describing major groups involved in narcosis and then subsequent rules can be developed for selecting the appropriate model for an analysis [1]. For example, QSARs have been created for phenols, which are a type of polar narcotic. These QSARs are based on both pKa and log Kow descriptors [2][13][10][7]. QSARs can be assumed to successfully relate a Kow to solubility in lipids within organisms, however there has been a wide range of error in this assumption for polar narcotics [7][14][11]. In predicting chronic toxicity to fish, QSARs are limited to the Ecological Structure Activity Relationships model (ECOSAR) in which a linear regression is created depicting the relationship between the log Kow and toxicity [13]. On a broader scale, more accurate QSARs will better provide insights into toxicological mechanisms due to their better simulation of basic toxicological processes [1]. Currently predicting the mode of action for a particular chemical remains difficult [10]. However, in order to create more advanced QSARs, there is a need for a greater understanding of chemical data, such as rates of metabolic biotransformation [2][9][7]. 

Environmental Management

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By using a combination of fish acute toxicity syndrome (FATS) test data and quantitative structure-activity relationship (QSAR) regression models, Narcosis I and Narcosis II can establish baseline toxicity guidelines to be use in fields such as risk assessment and environmental management. The QSAR model allows for the endpoint data obtained from FATS tests such as LC50’s or EC50’s to be compared with environmental chemistry data including the Logarithmic (logarithm) Water-Octanol partitioning coefficient (Kow), the Bioconcentration factor (BCF), and the Critical Body Residue (CBR). Regulatory groups can use this model to analyze how the toxicity of a chemical changes with the distribution of molecules thus resulting in a change in the structure-activity relationship.

Baseline toxicity data can be established by analyzing regression models to set a predicted level of maximum toxicant. The appropriate maximum concentration of the toxicant is then used in regulation to establish safe levels of concentrations below the that level [3]. It is important to note that for regulation purposes that if polar and non-polar narcotics produce similar effects, the baseline toxicity should be set for non-polar narcotics since polar narcotics have exhibited greater toxicity than predicted by baseline toxicity models [9]

Additionally, the use of QSARs can provide researchers with an alternative to live organism toxicity tests which reduces the number of individuals used in potentially expensive and painful toxicity tests. [13] This also adds data to databases where comparisons and read-across data analysis is possible.

References

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[1] [2] [5] [13] [12] [4] [9] [10] [7] [6] [3] [14] [11] [15] [16] [17] [19] [8] [18]

  1. ^ a b c d e f g h i j k l m n o p q r s t u v w x y Veith, G.D., Broderius, S.J. (1990). "Rules for distinguishing toxicants that cause type I and type II narcosis syndromes". Environmental Health Perspectives: 207–211. {{cite journal}}: Cite journal requires |journal= (help)CS1 maint: multiple names: authors list (link)
  2. ^ a b c d e f g h i j k l m n o p q r s t u v w x y Bradbury, S.P., Russom, C.L., Ankley, G.T., Schultz, T.W., Walker, J.D (2003). "Overview Of Data And Conceptual Approaches For Derivation Of Quantitative Structure–Activity Relationships For Ecotoxicological Effects Of Organic Chemicals". Environmental Toxicology and Chemistry: 1789. {{cite journal}}: Cite journal requires |journal= (help)CS1 maint: multiple names: authors list (link)
  3. ^ a b c d e f g h i j k l m n o p Ferguson, J. (1939). "The Use of Chemical Potentials as Indices of Toxicity". Proceedings of the Royal Society B: Biological Sciences.: 387–404. {{cite journal}}: Cite journal requires |journal= (help)
  4. ^ a b c d e f g Vaes, W.H., Ramos, E.U., Verhaar, H.J., Hermens, J.L. (1998). "Acute Toxicity Of Nonpolar Versus Polar Narcosis: Is There A Difference?". Environmental Toxicology and Chemistry. {{cite journal}}: Cite journal requires |journal= (help)CS1 maint: multiple names: authors list (link)
  5. ^ a b c d e f g h i j k l m n o p q r s t u Ankley, G.T., Bennett, R.S., Erickson, R.J., Hoff, D.J., Hornung, M.W., Johnson, R.D., Mount, D.R., Nichols, J.W., Russom, C.L., Schmieder, P.K., Serrano, J.A., Tietge, J.E., Villeneuve, D.L., Broderius, S.J. (2010). "Adverse outcome pathways: A conceptual framework to support ecotoxicology research and risk assessment". Environmental Toxicology and Chemistry: 730–741. {{cite journal}}: Cite journal requires |journal= (help)CS1 maint: multiple names: authors list (link)
  6. ^ a b c d e f g h i j Broderius, S.J., Kahl, M.D., Elonen, G.E., Hammermeister, D.E., Hoglund, M.D. (2005). "A Comparison Of The Lethal And Sublethal Toxicity Of Organic Chemical Mixtures To The Fathead Minnow (Pimephales Promelas)". Environmental Toxicology and Chemistry: 3117. {{cite journal}}: Cite journal requires |journal= (help)CS1 maint: multiple names: authors list (link)
  7. ^ a b c d e f g Mackay, D., Arnot, J., Celsie, A., Orazietti, A., Parnis, J. (2014). "QSARs for aquatic toxicity: celebrating, extending and displaying the pioneering contributions of Ferguson, Konemann and Veith". SAR and QSAR in Environmental Research: 343–355. {{cite journal}}: Cite journal requires |journal= (help)CS1 maint: multiple names: authors list (link)
  8. ^ a b c d e f Rand, G.M., Anderson, D.P., Balk, F.; et al. (1995). "Fundamentals of Aquatic Toxicology; Effects, Environmental Fate, and Risk Assessment". Boca Raton: CRC Publisher. {{cite journal}}: Cite journal requires |journal= (help); Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  9. ^ a b c d e f g h i j k l m n o p q r Bradbury, S.P., Carlson, R.W., Henry, T.R. (1989). "Polar Narcosis in Aquatic Organisms". Aquatic Toxicology and Hazard Assessment. {{cite journal}}: Cite journal requires |journal= (help)CS1 maint: multiple names: authors list (link)
  10. ^ a b c d e f g h Veith, G.D., Call, D.J., Brooke, L.T. (1983). "Structure–Toxicity Relationships for the Fathead Minnow, Pimephales promelas: Narcotic Industrial Chemicals". Canadian Journal of Fisheries and Aquatic Sciences. {{cite journal}}: Cite journal requires |journal= (help)CS1 maint: multiple names: authors list (link)
  11. ^ a b c d e f g h i j k l m n o p Raevsky, O.A., Grigorev, V.Y., Weber, E.E., Dearden, J.C. (2008). "Classification and Quantification of the Toxicity of Chemicals to Guppy, Fathead Minnow and Rainbow". {{cite journal}}: Cite journal requires |journal= (help)CS1 maint: multiple names: authors list (link)
  12. ^ a b c d e f g h i Verhaar, H.J.M., Ramos, E.U., Hermens, J.L.M. (1996). "Classifying environmental pollutants. 2: Separation of class 1 (baseline toxicity) and class 2 ('polar narcosis') type compounds based on chemical descriptors". Journal of Chemometrics: 149–162. {{cite journal}}: Cite journal requires |journal= (help)CS1 maint: multiple names: authors list (link)
  13. ^ a b c d e f g h i j k l m n o p Claeys, L., Iaccino, F., Janssen, C.R., Sprang, P.V., Verdonck, F., Tietge, J.E. (2013). "Development and validation of a quantitative structure-activity relationship for chronic narcosis to fish". Environmental Toxicology and Chemistry: 2217–2225. {{cite journal}}: Cite journal requires |journal= (help)CS1 maint: multiple names: authors list (link)
  14. ^ a b c Ramos, E.U., Vaes, W.H.J., Verhaar, H.J.M., Hermens, J.L.M. (1997). "Polar narcosis: Designing a suitable training set for QSAR studies". Environmental Science and Pollution Research: 83–90. {{cite journal}}: Cite journal requires |journal= (help)CS1 maint: multiple names: authors list (link)
  15. ^ a b U.S Government Accountability Office (2013). "EPA has increased efforts to assess and control chemicals but could strengthen its approach ". {{cite journal}}: Cite journal requires |journal= (help)
  16. ^ a b c Hemond, H. F., & Fechner-Levy, E. J. (2013). "Chemical Fate and Transport in the Environment". Amsterdam: Elsevier/AP, Academic Press is an imprint of Elsevier. {{cite journal}}: Cite journal requires |journal= (help)CS1 maint: multiple names: authors list (link)
  17. ^ a b c d e f Landis, W.G., Sofield, R.M., Yu, M.H. (2017). "Introduction to Environmental Toxicology Molecular Substructures to Ecological Landscapes, 5th ed". Boca Raton: CRC Press. {{cite journal}}: Cite journal requires |journal= (help)CS1 maint: multiple names: authors list (link)
  18. ^ a b c d Mccarty, L., Mackay, D., Smith, A. (1992). "Residue‐Based Interpretation of Toxicity and Bioconcentration QSARs from Aquatic Bioassays: Neutral Narcotic Organics". Environmental Toxicology and Chemistry: 1037-1047. {{cite journal}}: Cite journal requires |journal= (help)CS1 maint: multiple names: authors list (link)
  19. ^ Roberts, D., Costello, J. (2017). "Mechanisms of Action for General and Polar Narcosis: A Difference in Dimension". QSAR and Combinatorial Science. {{cite journal}}: Cite journal requires |journal= (help)CS1 maint: multiple names: authors list (link)
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