Environmental Categorization and Screening of the DSL Substances

Inherently ToxicPersistent

orBioaccumulative

Screening Assessment

Add to Schedule 1List of Toxic Substances forPossible Regulatory Actions

No Further Actionat this Time

Substances on the DSL

and

NoYes

PHASE 1:Categorization

PHASE 2:Screening levelrisk assessment

Outcomes

nofurther action

under thisprogram

Is the Substance a

Track 1 Substance?

Add to the Priority Substances List for

Further Assessment

Criteria for Inherently toxic (iT) in CEPA, UNEP

Proposed iT criteria for non-human organisms

– aquatic acute effects levels of < 1 mg/L

– above 1 mg/L professional judgment considering other factors (e.g. molecular weight, metabolism...)

– log Kow > 6 (consideration of effects to wildlife)

“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

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

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

Hexachlorobenzene 5.5 none

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

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

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

Hexachlorobenzene 5.5 none

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

Criteria for Inherently toxic (iT) in CEPA, UNEP

Proposed iT criteria for non-human organisms

– aquatic acute effects levels of < 1 mg/L

– above 1 mg/L professional judgment considering other factors (e.g. molecular weight, metabolism...)

– log Kow > 6 (consideration of effects to wildlife)

1 mg/L

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

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

Hexachlorobenzene 5.5 none

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

Potency

Exposure

Effect

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

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.

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.

0

500

1000

1500

2000

2500

3000

3500

4000

4500

0 5 10 15

Time (days)

Co

nce

ntr

atio

n (

pg

/kg

)

1 pg/L

0.5 pg/L

0.1 pg/L

1

0.5

0.1

Water Concentration

pg/L

Acute vs. Chronic Toxicity

Lethal Body burden

Mixtures of Chemicals

For chemicals that share Non-Polar Narcosis Mode of Toxic Action:

If

cinternal > 5 mmol/kg

Then

50% lethality

For Chemicals Acting by Non-Polar Narcosis

Mixture Toxicity

cinternal > ~ 5 mmol/kg)

Dioxin Toxicity in Lake Trout

Dose-Response Curve for TCDD

Substances with Dioxin-like Toxicity

Dioxin Toxicity

10 Angstrom

4 Angstrom

+ Aryl Hydrocarbon Receptor

Mechanism of Toxic Action

Cytochrome P450

Cycle

Phase I Reaction

Phase II Reaction

Role of Cytochrome P450 in Bioactivation

For Chemicals with Dioxin like mode of toxic action

Dioxin-like Mixture Toxicity

Toxic Equivalent Concentration (ng/kg) =

(CPCDDi × TEFi) + (CPCDFi × TEFi) + (CPCBi × TEFi)

Recipe for a Toxic Effect

•Ingredients :

•Exposure:

Relationship between external concentration and the concentration at the active site

•Potency :

concentration at the active site required to trigger the effect

•Directions:

•concentration at the active site > concentration at the active site required to trigger the effect

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(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)

Acute vs. Chronic Toxicity

0

500

1000

1500

2000

2500

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3500

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0 5 10 15

Time (days)

Co

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n (

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/kg

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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??

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?

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??

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?

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 =

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

Risk

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

.000

.009

.018

.028

.037

0

46

92

138

184

-0.75 -0.13 0.50 1.13 1.75

Forecast: B4

Example:

LC5 = 50 ng/L

Exposure Concentration : 30 15 ng/L (normal)

8.3%

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

.000

.013

.026

.039

.052

0

64.7

129

194

259

0.00 1.00 2.00 3.00 4.00

Forecast: B4

22%