“The Dose makes the Poison” Paracelcus (1567). What is "Toxicity”?

transcript

“The Dose makes the Poison”

Paracelcus (1567)

What is "Toxicity”?

TOXICITY IN GUPPIES(From : data from Abernethy et al. 1987)

Chemical log Kow LC50(umol/L)

Monochlorobenzene 2.8 170

Dichlorobenzene 3.4 50

Trichlorobenzene 4 12

Tetrachlorobenzene 4.5 3.7

Pentachlorobenzene 5 1

Hexachlorobenzene 5.5 none

Lipid Content of the guppies : 4%Solubility of Hexachlorobenzene in water: 1.7.10^-5 mmol/L

Chemical log Kow LC50 Cfish(umol/L) (umol/kg)

Monochlorobenzene 2.8 170 4291

Dichlorobenzene 3.4 50 5024

Trichlorobenzene 4 12 4800

Tetrachlorobenzene 4.5 3.7 4680

Pentachlorobenzene 5 1 4000

Chemical log Kow LC50 Cfish(umol/L) (umol/kg)

Monochlorobenzene 2.8 170 4291

Dichlorobenzene 3.4 50 5024

Trichlorobenzene 4 12 4800

Tetrachlorobenzene 4.5 3.7 4680

Pentachlorobenzene 5 1 4000

Internal concentrationfor acute toxicity : 5 mmol/kg

Fish-water Bioconcentration Factor : 0.04 8 105.5 = 12,600

Water Concentration needed : 5 / 12,600 = 4 .10-4 mmol/L

Water Solubility : 1.7 .10-5 mmol/L

Ferguson cut-off

Chemical concentration in the water that is required to produce the internal concentration in the organism that is needed to trigger the effect exceeds the chemical’s water solubility.

Toxic Effect = f(concentration at the active site, concentration at the active site required to trigger the effect)

Toxic Effect = f(EXPOSURE, POTENCY)

Toxic Effect = f(EXPOSURE, TOXICITY)

What is the difference?

•Dose makes the Poison

•Toxic Effect = f(concentration at the active site, concentration at the active site required to trigger the effect)

What is the difference?

•Dose makes the Poison

•Toxic Effect = f(concentration at the active site, concentration at the active site required to trigger the effect)

External

Internal

To agree or not agree?

Chemicals that cause the same effect at the same internal concentration have the same potency / toxicity

Non-Polar Narcosis

similarity with anesthetics: chloroform

Lethality at an internal concentration: 3 to 6 mmol/kg

All chemicals & all organisms

mechanism unknown

likely affect membranes:

swells membranes causing a physical effect

affects membrane proteins

Narcosis is the most basic mode of toxic action.

Chemicals will have at least this toxicity or they may have

a greater toxicity.

FISH 1 FISH 2

Volume Total (m3) 1 1Volume Water (m3) 0.9 0.5Volume Lipid (m3) 0.1 0.5Concentration in water 1.10-6 1.10-6

(mol/m3)

ZW 1 1fW 1.10-6 1.10-6

fL 1.10-6 1.10-6

ZL 104 104

Cw 1.10-6 1.10-6

CL 1.10-2 1.10-2

VW.CW 0.9 . 10-6 0.5 . 10-6

VL.CL 0.1 . 10-2 0.5 . 10-2

Vi.Ci ~0.1 . 10-2 ~0.5 . 10-2

Ci ~0.1 . 10-2 ~0.5 . 10-2

Toxic Effect =

f(fugacity at the active site, fugacity at the active site associated with the effect)

f(f at the active site, f at the active site associated with the effect)

Toxic Effect =

f(f at the active site, f at the active site associated with the effect)

Acute vs. Chronic Toxicity

0 5 10 15

Time (days)

1 pg/L

0.5 pg/L

0.1 pg/L

So what??

You want to protect all aquatic life by setting a water quality criterion for chemical X, i.e. a water concentration that should not be exceeded.

So, what do you do?

So what??

So, what do you do?

This WQC is derived from a study of LC50 or NOAEC derived in the lab, and you take the lowest LC50 divide it by a safety factor (e.g. 10), and this becomes your criterion.

So what??

So, what do you do?

This WQC is derived from a study of LC50 or NOAEC derived in the lab, and you take the lowest LC50 divide it by a safety factor (e.g. 10), and this becomes your criterion.

Then you manage environmental quality by a monitoring program that measures water concentrations & compares them with the WQC.

Tissue Residue Approach for Characterizing Toxicity

Merits:

eliminates transport/bioaccumulation from the external environment (Exposure), including:

•bioavailability

•dietary uptake and biomagnification

•metabolism

•accumulation kinetics

Mixtures of Chemicals

If Shared Mode of Toxic Action:

Toxic Effect = f(Cinternal, Potency)

Species Differences

Toxic Effect =

Dose - Response Relationship

Application of Toxicity Data to conduct Hazard and Risk Assessment

General Problem:

The Concentration of Trichlorobenzene in River Water is: 5.10-6 mmol/L

LC50 in guppies (48 hr) : 5.10-4 mmol/kg

What is the hazard and/or risk to rainbow trout?

Application of Toxicity Data to conduct Hazard and Risk Assessment

General Problem:

The ingested dose of Trichlorobenzene by (humans or sea otters) in food items is: 5.10-2 mg/kg/day

LD50 in rats (14 days) : 50 mg/kg/day

LOAEL : 5 mg/kg/day

What is the hazard and/or risk to humans or sea otters?

Hazard :

Potential for a toxicological effect occurring

Assessment of Hazard

Reference Dose

Is an estimate of the daily dose to a population that is unlikely to produce an appreciable risk of adverse effect during a life time. Similar to an acceptable daily intake.

Reference Concentration

Is an estimate of the concentrations to a population that is unlikely to produce an appreciable risk of adverse effect during a life time. Similar to an acceptable concentration.

Hazard Index

H = dose / Rfd

< 1.0 There is no hazard

> 1.0 There is a hazard

Hazard Index

Rfd = 5 mg/kg/day(LOAEL)/1000 = 5.10-3

H = 5.10-2 / 5.10-3 = 10

There is a hazard

> 1.0 There is a hazard

Probability of a toxicological effect occuring

Single-Point Exposure and Effects Comparison

Quotient-Method

•Cexposure / Ceffect

•Ceffects can be: LC50, LD50, EC50, NOAEL, LOAEL, LC5 etc.

•Sometimes combined with a safety-factor

Example:

LC5 = 50 ng/L

Exposure Concentration : 30 ng/L

Cexposure/LC5 = 60%

Cell B4 Frequency Chart

Certainty Range is from -Infinity to 1.00

5,000 Trials Shown

-0.75 -0.13 0.50 1.13 1.75

Forecast: B4

Example:

LC5 = 50 ng/L

Exposure Concentration : 30 15 ng/L (normal)

Example:

LC5 = 50 ng/L

Exposure Concentration : 30 15 ng/L (log-normal)

Cell B4 Frequency Chart

Certainty Range is from -Infinity to 1.00

4,990 Trials Shown

0.00 1.00 2.00 3.00 4.00

Forecast: B4

“The Dose makes the Poison” Paracelcus (1567). What is "Toxicity”?

Documents